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Shang Y, He Y, Zhang X, He W, Hua H, Ye F, Zhou X, Li Y, Zhong W, Wu G, Jiang W. Optimization of Immunotherapy Strategies Based on Spatiotemporal Heterogeneity of Tumour-Associated Tissue-Resident Memory T Cells. Immunology 2025; 175:123-133. [PMID: 40114407 PMCID: PMC12052439 DOI: 10.1111/imm.13924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 02/26/2025] [Accepted: 03/11/2025] [Indexed: 03/22/2025] Open
Abstract
Tissue-resident memory T cells (TRMs) reside in peripheral tissues and provide rapid immune defence against local infection and tumours. Tumour-associated TRMs share common tissue-resident features and formation mechanisms, representing some unique subsets of tumour-infiltrating lymphocytes (TILs). However, differences in the tumour microenvironment(TME) and tumour evolution stage result in TRMs exhibiting temporal and spatial heterogeneity of phenotype and function not only at different stages, before and after treatment, but also between tumours originating from different tissues, primary and metastatic cancer, and tumour and adjacent normal tissue. The infiltration of TRMs is often associated with immunotherapy response and favourable prognosis; however, due to different definitions, it has been shown that some subtypes of TRMs can also have a negative impact. Therefore, it is crucial to precisely characterise the TRM subpopulations that can influence the therapeutic efficacy and clinical prognosis of various solid tumours. Here, we review the spatiotemporal heterogeneity of tumour-associated TRMs, as well as the differences in their impact on clinical outcomes. We also explore the relationship between TRMs and immune checkpoint blockade (ICB) and TIL therapy, providing insights into potential new targets and strategies for immunotherapy.
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Affiliation(s)
- Yile Shang
- Department of Colorectal Surgery, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- College of MedicineZhejiang UniversityHangzhouChina
| | - Yinjun He
- College of MedicineZhejiang UniversityHangzhouChina
| | - Xiang Zhang
- Department of Colorectal Surgery, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Wenguang He
- Department of Radiology, First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Hanju Hua
- Department of Colorectal Surgery, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Feng Ye
- Department of Colorectal Surgery, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xile Zhou
- Department of Colorectal Surgery, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Yandong Li
- Department of Colorectal Surgery, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Weixiang Zhong
- Department of Pathology, First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Guosheng Wu
- Department of Colorectal Surgery, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Weiqin Jiang
- Department of Colorectal Surgery, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
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Ran R, Chen X, Yang J, Xu B. Immunotherapy in breast cancer: current landscape and emerging trends. Exp Hematol Oncol 2025; 14:77. [PMID: 40405250 PMCID: PMC12096519 DOI: 10.1186/s40164-025-00667-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Accepted: 05/08/2025] [Indexed: 05/24/2025] Open
Abstract
Breast cancer remains one of the most prevalent malignancies worldwide, underscoring an urgent need for innovative therapeutic strategies. Immunotherapy has emerged as a transformative frontier in this context. In triple-negative breast cancer (TNBC), the combination of immunotherapy based on PD-1/PD-L1 immune checkpoint inhibitors (ICIs) with chemotherapy has proven efficacious in both early and advanced clinical trials. These encouraging results have led to the approval of ICIs for TNBC, opening up new therapeutic avenues for challenging-to-treat patient populations. Furthermore, a multitude of ongoing trials are actively investigating the efficacy of immunotherapy-based combinations, including ICIs in conjunction with chemotherapy, targeted therapy and radiation therapy, as well as other novel strategies such as bispecific antibodies, CAR-T cells and cancer vaccines across all breast cancer subtypes, including HR-positive/HER2-negative and HER2-positive disease. This review provides a comprehensive overview of current immunotherapeutic approaches in breast cancer, highlighting pivotal findings from recent clinical trials and the potential impact of these advancements on patient outcomes.
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Affiliation(s)
- Ran Ran
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xi Chen
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jin Yang
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Binghe Xu
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
- National Cancer Center, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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3
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Cheung AM, Wang D, Quintayo MA, Yerofeyeva Y, Spears M, Bartlett JMS, Stein L, Bayani J, Yaffe MJ. Intra-tumoral spatial heterogeneity in breast cancer quantified using high-dimensional protein multiplexing and single cell phenotyping. Breast Cancer Res 2025; 27:88. [PMID: 40399910 PMCID: PMC12096620 DOI: 10.1186/s13058-025-02038-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 04/29/2025] [Indexed: 05/23/2025] Open
Abstract
BACKGROUND Breast cancer is a highly heterogeneous disease where variations of biomarker expression may exist between individual foci of a cancer (intra-tumoral heterogeneity). The extent of variation of biomarker expression in the cancer cells, distribution of cell types in the local tumor microenvironment and their spatial arrangement could impact on diagnosis, treatment planning and subsequent response to treatment. METHODS Using quantitative multiplex immunofluorescence (MxIF) imaging, we assessed the level of variations in biomarker expression levels among individual cells, density of cell cluster groups and spatial arrangement of immune subsets from regions sampled from 38 multi-focal breast cancers that were processed using whole-mount histopathology techniques. Molecular profiling was conducted to determine the intrinsic molecular subtype of each analysed region. RESULTS A subset of cancers (34.2%) showed intra-tumoral regions with more than one molecular subtype classification. High levels of intra-tumoral variations in biomarker expression levels were observed in the majority of cancers studied, particularly in Luminal A cancers. HER2 expression quantified with MxIF did not correlate well with HER2 gene expression, nor with clinical HER2 scores. Unsupervised clustering revealed the presence of various cell clusters with unique IHC4 protein co-expression patterns and the composition of these clusters were mostly similar among intra-tumoral regions. MxIF with immune markers and image patch analysis classified immune niche phenotypes and the prevalence of each phenotype in breast cancer subtypes was illustrated. CONCLUSIONS Our work illustrates the extent of spatial heterogeneity in biomarker expression and immune phenotypes, and highlights the importance of a comprehensive spatial assessment of the disease for prognosis and treatment planning.
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Affiliation(s)
- Alison M Cheung
- Biomarker Imaging Research Lab (BIRL), Sunnybrook Research Institute, Rm S658, 2075 Bayview Avenue, Toronto, ON, Canada
| | - Dan Wang
- Biomarker Imaging Research Lab (BIRL), Sunnybrook Research Institute, Rm S658, 2075 Bayview Avenue, Toronto, ON, Canada
| | - Mary Anne Quintayo
- Diagnostic Development, Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Yulia Yerofeyeva
- Biomarker Imaging Research Lab (BIRL), Sunnybrook Research Institute, Rm S658, 2075 Bayview Avenue, Toronto, ON, Canada
| | - Melanie Spears
- Diagnostic Development, Ontario Institute for Cancer Research, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - John M S Bartlett
- Diagnostic Development, Ontario Institute for Cancer Research, Toronto, ON, Canada
- University of Edinburgh, Edinburgh, UK
| | - Lincoln Stein
- Informatics and Bio-Computing, Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Jane Bayani
- Diagnostic Development, Ontario Institute for Cancer Research, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Martin J Yaffe
- Biomarker Imaging Research Lab (BIRL), Sunnybrook Research Institute, Rm S658, 2075 Bayview Avenue, Toronto, ON, Canada.
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
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4
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Taurelli Salimbeni B, Giudici F, Pescia C, Berton Giachetti PPM, Scafetta R, Zagami P, Marra A, Trapani D, Esposito A, Scagnoli S, Cerbelli B, Botticelli A, Munzone E, Fusco N, Criscitiello C, Curigliano G. Prognostic impact of tumor-infiltrating lymphocytes in HER2+ metastatic breast cancer receiving first-line treatment. NPJ Breast Cancer 2025; 11:41. [PMID: 40346114 PMCID: PMC12064824 DOI: 10.1038/s41523-025-00760-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 04/21/2025] [Indexed: 05/11/2025] Open
Abstract
Breast cancer (BC) is a leading cause of death among women, with approximately 30% HER2-positive (HER2+). Although HER2-targeted therapies have improved outcomes for patients with HER2+ metastatic breast cancer (mBC), clinical challenges and prognostic variability remain. Tumor-infiltrating lymphocytes (TILs) have emerged as prognostic and predictive biomarkers in various tumors, including BC, but their role in HER2+ mBC is poorly understood. This multicentric retrospective cohort study evaluated the prognostic significance of TILs in 110 patients with HER2+ mBC treated with pertuzumab, trastuzumab, and taxane-based chemotherapy at two Italian institutes from June 2013 to May 2024. TILs were assessed on metastatic or primary tumor samples. High TILs levels (>5%) were independently associated with longer PFS and OS. TILs levels were higher in primary tumours than in metastases (p = 0.009), with significant variation by metastatic site. These findings underscore the potential of TILs as prognostic biomarkers in HER2+ mBC, necessitating further prospective studies.
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Affiliation(s)
- Beatrice Taurelli Salimbeni
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy.
| | - Fabiola Giudici
- Cancer Epidemiology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Carlo Pescia
- Division of Pathology, European Institute of Oncology IRCCS, Milan, Italy
- Division of Pathology, ASST Santi Paolo e Carlo, Milan, Italy
| | - Pier Paolo Maria Berton Giachetti
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Haemato-Oncology, University of Milan, Milan, Italy
| | - Roberta Scafetta
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
- Medical Oncology Department, Campus Bio-Medico University of Rome, Rome, Italy
| | - Paola Zagami
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Haemato-Oncology, University of Milan, Milan, Italy
| | - Antonio Marra
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Haemato-Oncology, University of Milan, Milan, Italy
| | - Dario Trapani
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Haemato-Oncology, University of Milan, Milan, Italy
| | - Angela Esposito
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
| | - Simone Scagnoli
- Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy
| | - Bruna Cerbelli
- Department of Medico-surgical Sciences and Biotechnologies, Sapienza, University of Rome, Rome, Italy
| | - Andrea Botticelli
- Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy
| | - Elisabetta Munzone
- Division of Medical Senology, European Institute of Oncology IRCCS, Milan, Italy
| | - Nicola Fusco
- Division of Pathology, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Haemato-Oncology, University of Milan, Milan, Italy
| | - Carmen Criscitiello
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Haemato-Oncology, University of Milan, Milan, Italy
| | - Giuseppe Curigliano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Haemato-Oncology, University of Milan, Milan, Italy
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5
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Alemu BK, Tommasi S, Hulin JA, Meyers J, Mangoni AA. Current knowledge on the mechanisms underpinning vasculogenic mimicry in triple negative breast cancer and the emerging role of nitric oxide. Biomed Pharmacother 2025; 186:118013. [PMID: 40147105 DOI: 10.1016/j.biopha.2025.118013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 03/13/2025] [Accepted: 03/24/2025] [Indexed: 03/29/2025] Open
Abstract
Vasculogenic mimicry (VM) is the process by which cancer cells form vascular-like channels to support their growth and dissemination. These channels lack endothelial cells and are instead lined by the tumour cells themselves. VM was first reported in uveal melanomas but has since been associated with other aggressive solid tumours, such as triple-negative breast cancer (TNBC). In TNBC patients, VM is associated with tumour aggressiveness, drug resistance, metastatic burden, and poor prognosis. The lack of effective targeted therapies for TNBC has stimulated research on the mechanisms underpinning VM in order to identify novel druggable targets. In recent years, studies have highlighted the role of nitric oxide (NO), the NO synthesis inhibitor, asymmetric dimethylarginine (ADMA), and dimethylarginine dimethylaminohydrolase 1 (DDAH1), the key enzyme responsible for ADMA metabolism, in regulating VM. Specifically, NO inhibition through downregulation of DDAH1 and consequent accumulation of ADMA appears to be a promising strategy to suppress VM in TNBC. This review discusses the current knowledge regarding the molecular pathways underpinning VM in TNBC, anti-VM therapies under investigation, and the emerging role of NO regulation in VM.
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Affiliation(s)
- Belete Kassa Alemu
- Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Adelaide, South Australia, Australia; Injibara University, College of Medicine and Health Sciences, Department of Pharmacy, Injibara, Ethiopia
| | - Sara Tommasi
- Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Adelaide, South Australia, Australia; Department of Clinical Pharmacology, Flinders Medical Centre, Southern Adelaide Local Health Network, Adelaide, Australia
| | - Julie-Ann Hulin
- Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Jai Meyers
- Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Arduino A Mangoni
- Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Adelaide, South Australia, Australia; Department of Clinical Pharmacology, Flinders Medical Centre, Southern Adelaide Local Health Network, Adelaide, Australia.
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6
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Wang X, Wang L, Liu Y. Current Status of Immune Checkpoint Inhibitors and Treatment Responsive Biomarkers for Triple-Negative Breast Cancer. Thorac Cancer 2025; 16:e70072. [PMID: 40324951 PMCID: PMC12052518 DOI: 10.1111/1759-7714.70072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 03/24/2025] [Accepted: 04/15/2025] [Indexed: 05/07/2025] Open
Abstract
Triple-negative breast cancer (TNBC), accounting for about 10%-20% of all breast cancer cases, is characterized by its aggressive nature, high recurrence rates, and poor prognosis. Unlike other breast cancer subtypes, TNBC lacks hormone receptors and specific molecular targets, limiting therapeutic options. In recent years, immune checkpoint inhibitors (ICIs) have shown promise in treating TNBC by targeting immune evasion mechanisms. Despite these advancements, several issues remain unresolved, including low response rates in programmed cell death ligand 1 (PD-L1) negative TNBC subtypes and the challenge of predicting which patients will benefit from ICIs. Consequently, there is growing interest in identifying reliable biomarkers beyond PD-L1 expression. This review synthesizes recent studies to provide a comprehensive perspective on ICI therapy in TNBC, clarifying the status of single-agent ICI therapies and combination strategies, emphasizing the need for further research into biomarkers. These insights provide clues for more personalized and effective treatment approaches, ultimately aiming to improve clinical outcomes for patients with TNBC.
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Affiliation(s)
- Xinran Wang
- Department of PathologyThe Fourth Hospital of Hebei Medical UniversityShijiazhuangHebeiChina
| | - Lingxia Wang
- Value & Implementation, Global Medical & Scientific AffairsMSD ChinaShanghaiChina
| | - Yueping Liu
- Department of PathologyThe Fourth Hospital of Hebei Medical UniversityShijiazhuangHebeiChina
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7
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Caluwé AD, Bellal S, Cao K, Peignaux K, Remouchamps V, Baten A, Longton E, Bessieres I, Vu-Bezin J, Kirova Y, Gestel DV, Desmoulins I, Ignatiadis M, Romano E, Buisseret L, Piccart M, Vandekerkhove C, Gulyban A, Poortmans P. Adapting radiation therapy to immunotherapy: Delineation and treatment planning of pre-operative immune-modulating breast iSBRT in 151 patients treated in the randomized phase II Neo-CheckRay trial. Radiother Oncol 2025; 206:110836. [PMID: 40057199 DOI: 10.1016/j.radonc.2025.110836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 02/17/2025] [Accepted: 03/01/2025] [Indexed: 04/20/2025]
Abstract
BACKGROUND AND PURPOSE The randomized multicentric phase II Neo-CheckRay trial investigated preoperative immune-modulating stereotactic body radiation therapy (iSBRT) 8 Gy x 3 fractions in combination with chemotherapy with or without the anti PD-L1 durvalumab and the anti-CD73 oleclumab in early-stage, high-risk, luminal B breast cancer. iSBRT was solely delivered to the primary breast cancer leveraging on its immune modulating potential to sustain an anti-tumour response. To avoid immunosuppression induced by radiation therapy (RT), the tumour draining lymph nodes (TDLN) were spared. Here, we present the constraints used in the Neo-CheckRay trial and a dosimetric analysis of all delivered treatment plans with a special focus on the dose to the TDLN. MATERIALS AND METHODS Main constraints were the skin (D0.1 cc < 19.2 Gy), chest wall (D1cc < 15 Gy) and ipsilateral uninvolved breast (V24Gy < 30 %). The dose to the TDLN was reduced by avoiding beams entering or exiting the TDLN. In the present work, the DICOM-RT data of all the patients treated in the Neo-CheckRay trial were collected (n = 151) to describe doses to the target volume, to the organs at risk and the TDLN. The TDLN volumes consisted of the internal mammary nodes (IMN) and the axilla levels I-IV including the interpectoral nodes. RESULTS In 151 patients, the median V95% of the gross target volume (GTV) and planning target volume (PTV) were 97.4 % (90 % CI 26.5-100) and 95.5 % (56.1-100). The mean dose (dMean) to all TDLN volumes was < 1 Gy. The highest dMean were to the IMN and axilla level 1: 0.8 Gy (90 % CI 0.1-2.7) and 0.6 Gy (0.0-3.9), respectively. The dMean to the involved lymph nodes, if present, was 0.3 Gy (0.0-5.0). CONCLUSION In the Neo-CheckRay trial, the predefined organs at risk dose constraints were feasible and the TDLN were adequately spared.
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Affiliation(s)
- A De Caluwé
- Jules Bordet Institute, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium.
| | - S Bellal
- Jules Bordet Institute, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium
| | - K Cao
- Institut Curie, Paris, France
| | - K Peignaux
- Centre George François Leclerc, Dijon, France
| | - V Remouchamps
- Clinique Hospitalier Universitaire CHU UCL St. Elisabeth, Namur, Belgium
| | - A Baten
- Universitaire Ziekenhuizen Leuven, Leuven, Belgium
| | - E Longton
- Cliniques Universitaires St. Luc, Brussels, Belgium
| | - I Bessieres
- Centre George François Leclerc, Dijon, France
| | | | | | - D Van Gestel
- Jules Bordet Institute, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium
| | | | - M Ignatiadis
- Jules Bordet Institute, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium
| | | | - L Buisseret
- Jules Bordet Institute, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium
| | - M Piccart
- Jules Bordet Institute, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium
| | - C Vandekerkhove
- Jules Bordet Institute, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium
| | - A Gulyban
- Jules Bordet Institute, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium
| | - P Poortmans
- Iridium Netwerk and University of Antwerp, Antwerp, Belgium
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8
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Luz P, Ramos S, Oliveira MJ, Costa JG, Saraiva N, Fernandes AS. Interaction between redox regulation, immune activation, and response to treatment in HER2+ breast cancer. Redox Biol 2025; 82:103609. [PMID: 40174475 PMCID: PMC11999322 DOI: 10.1016/j.redox.2025.103609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 03/21/2025] [Accepted: 03/21/2025] [Indexed: 04/04/2025] Open
Abstract
In HER2+ breast cancer (BC), neoadjuvant therapy represents an ideal scenario for translational research, considering pathological complete response (pCR) as an endpoint. In these patients, achieving pCR after neoadjuvant therapy is associated with a better prognosis. However, biomarkers are needed to tailor optimal treatment for each patient. Evaluating tumour-infiltrating lymphocytes (TILs) has gained attention in predicting pCR. In the context of metastatic disease, TILs also appear to play a role in predicting outcomes. The interaction between the presence of TILs and reactive oxygen species (ROS) remains an area to be explored. ROS are critical for tumour cell homeostasis, and different levels can trigger differential biological responses in cancer cells and their microenvironment. Nevertheless, the influence of ROS on treatment efficacy and prognosis in patients with HER2+ BC remains to be elucidated. In this article, we reviewed the interplay between treatment response, immune system activation, and ROS production in HER2+ BC and suggested novel areas of intervention and research. We also present a bioinformatic analysis demonstrating that the altered expression of several redox-related genes could be associated with the prevalence of immune cell populations in the tumour microenvironment and with patient survival. New biomarkers are thus suggested and should be further explored to tailor the best treatment to each patient.
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Affiliation(s)
- Paulo Luz
- CBIOS, Universidade Lusófona's Research Center for Biosciences & Health Technologies, Lisbon, Portugal; Universidad de Alcalá de Henares. Departamento de Ciencias Biomédicas, Alcalá de Henares, Madrid, Spain; Medical Oncology Department, Unidade Local de Saúde do Baixo Alentejo - Hospital José Joaquim Fernandes, Beja, Portugal
| | - Sofia Ramos
- CBIOS, Universidade Lusófona's Research Center for Biosciences & Health Technologies, Lisbon, Portugal; Universidad de Alcalá de Henares. Departamento de Ciencias Biomédicas, Alcalá de Henares, Madrid, Spain
| | - Maria José Oliveira
- i3S - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
| | - João G Costa
- CBIOS, Universidade Lusófona's Research Center for Biosciences & Health Technologies, Lisbon, Portugal
| | - Nuno Saraiva
- CBIOS, Universidade Lusófona's Research Center for Biosciences & Health Technologies, Lisbon, Portugal
| | - Ana S Fernandes
- CBIOS, Universidade Lusófona's Research Center for Biosciences & Health Technologies, Lisbon, Portugal.
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9
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Coleman C, Selvakumar T, Thurlapati A, Graf K, Pavuluri S, Mehrotra S, Sahin O, Sivapiragasam A. Harnessing Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Opportunities and Barriers to Clinical Integration. Int J Mol Sci 2025; 26:4292. [PMID: 40362529 PMCID: PMC12072607 DOI: 10.3390/ijms26094292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2025] [Revised: 04/23/2025] [Accepted: 04/29/2025] [Indexed: 05/15/2025] Open
Abstract
Triple-negative breast cancer (TNBC) continues to present a therapeutic challenge due to the fact that by definition, these cancer cells lack the expression of targetable receptors. Current treatment options include cytotoxic chemotherapy, antibody-drug conjugates (ADC), and the PD-1 checkpoint inhibitor, pembrolizumab. Due to high rates of recurrence, current guidelines for early-stage TNBC recommend either multi-agent chemotherapy or chemo-immunotherapy in all patients other than those with node-negative tumors < 0.5 cm. This approach can lead to significant long-term effects for TNBC survivors, driving a growing interest in de-escalating therapy where appropriate. Tumor infiltrating lymphocytes (TILs) represent a promising prognostic and predictive biomarker for TNBC. These diverse immune cells are present in the tumor microenvironment and within the tumor itself, and multiple retrospective studies have demonstrated that a higher number of TILs in early-stage TNBC portends a favorable prognosis. Research has also explored the potential of TIL scores to predict the response to immunotherapy. However, several barriers to the widespread use of TILs in clinical practice remain, including logistical and technical challenges with the scoring of TILs and lack of prospective trials to validate the trends seen in retrospective studies. This review will present the current understanding of the role of TILs in TNBC and discuss the future directions of TIL research.
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Affiliation(s)
- Cara Coleman
- Department of Hematology/Oncology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA (T.S.); (S.P.)
| | - Tharakeswari Selvakumar
- Department of Hematology/Oncology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA (T.S.); (S.P.)
| | - Aswani Thurlapati
- Department of Hematology/Oncology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA (T.S.); (S.P.)
| | - Kevin Graf
- Department of Hematology/Oncology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA (T.S.); (S.P.)
| | - Sushma Pavuluri
- Department of Hematology/Oncology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA (T.S.); (S.P.)
| | - Shikhar Mehrotra
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Ozgur Sahin
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA;
| | - Abirami Sivapiragasam
- Department of Hematology/Oncology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA (T.S.); (S.P.)
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Song L, Li X, Wang L, Cui J, Ma T. Prognostic and recurrence risk predictive values of tumor infiltrating lymphocytes in HER2-low breast cancer. Clin Transl Oncol 2025:10.1007/s12094-025-03921-1. [PMID: 40287914 DOI: 10.1007/s12094-025-03921-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Accepted: 03/30/2025] [Indexed: 04/29/2025]
Abstract
BACKGROUND With the emergence of novel anti-HER2 antibody drug conjugates, patients with HER2-low breast cancer have received increased attention. Tumor-infiltrating lymphocytes (TILs) are significantly associated with survival benefits in cancers. However, their prognostic value in patients with low her2 breast cancer is unknown. Therefore, we aimed to determine the relationship between TILs and recurrence in patients with HER2-low breast cancer. METHODS Clinicopathological data were retrospectively collected from patients with human epidermal growth factor receptor 2 (HER2) low-expression breast cancer who underwent consultations at Qingdao University Affiliated Hospital. We determined the correlation between TILs and disease-free survival (DFS) followed by the threshold value of TILs using X-tile software. Survival was assessed using Kaplan-Meier analysis, and cox regression analysis was performed for recurrence risk modeling. RESULTS Our study showed a 15% TIL level was the optimal cutoff for DFS. The low and high TILs survival curves showed significant differences in the log-rank test (p = 0.009). Cox regression analyses found that lymph node stage, histologic grading, TILs, and Ki-67 were independent variables influencing the prognosis (p < 0.05). On this basis, we developed a risk prediction model to accurately predict the 3- and 5-year disease-free survival rates of patients with HER2-low breast cancer, the model demonstrated good overall performance. CONCLUSION TILs are associated with recurrence in patients with breast cancer and low HER2 levels. TILs > 0.15 is a reliable indicator of DFS. For patients with low TILs (≤ 0.15), extensive follow-up is required. These findings provide a basis for targeted, individualized treatment.
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Affiliation(s)
- Lijun Song
- Breast Disease Center, Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong Province, China
- First Department of General Surgery, Weihaiwei People's Hospital, Weihai, 264200, Shandong Province, China
| | - Xiangjun Li
- Breast Disease Center, Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong Province, China
| | - Lulu Wang
- Department of Cardiovascular Surgery, Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong Province, China
| | - Jian Cui
- Breast Disease Center, Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong Province, China.
| | - Teng Ma
- Breast Disease Center, Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong Province, China.
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11
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Li H, Chang Y, Jin T, Zhang M. Progress of PD-1/PD-L1 immune checkpoint inhibitors in the treatment of triple-negative breast cancer. Cancer Cell Int 2025; 25:139. [PMID: 40211301 PMCID: PMC11987362 DOI: 10.1186/s12935-025-03769-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 03/28/2025] [Indexed: 04/13/2025] Open
Abstract
Triple-negative breast cancer (TNBC) is a highly heterogeneous cancer with substantial recurrence potential. Currently, surgery and chemotherapy are the main treatments for this disease. However, chemotherapy is often limited by several factors, including low bioavailability, significant systemic toxicity, inadequate targeting, and multidrug resistance. Immune checkpoint inhibitors (ICIs), including those targeting programmed death protein-1 (PD-1) and its ligand (PD-L1), have been proven effective in the treatment of various tumours. In particular, in the treatment of TNBC with PD-1/PD-L1 inhibitors, both monotherapy and combination chemotherapy, as well as targeted drugs and other therapeutic strategies, have broad therapeutic prospects. In addition, these inhibitors can participate in the tumour immune microenvironment (TIME) through blocking PD-1/PD-L1 binding, which can improve immune efficacy. This article provides an overview of the use of PD-1/PD-L1 inhibitors in the treatment of TNBC and the progress of multiple therapeutic studies. To increase the survival of TNBC patients, relevant biomarkers for predicting the efficacy of PD-1/PD-L1 inhibitor therapy have been explored to identify new strategies for the treatment of TNBC.
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Affiliation(s)
- Hongshu Li
- Department of Pathology and Cancer Research Center, Yanbian University Medical College, Gong Yuan Road No. 977, Yanji, 133002, P. R. China
- Key Laboratory of the Science and Technology Department of Jilin Province, Yanji, P. R. China
| | - Ying Chang
- Department of Pathology and Cancer Research Center, Yanbian University Medical College, Gong Yuan Road No. 977, Yanji, 133002, P. R. China
- Key Laboratory of the Science and Technology Department of Jilin Province, Yanji, P. R. China
| | - Tiefeng Jin
- Department of Pathology and Cancer Research Center, Yanbian University Medical College, Gong Yuan Road No. 977, Yanji, 133002, P. R. China.
- Key Laboratory of the Science and Technology Department of Jilin Province, Yanji, P. R. China.
| | - Meihua Zhang
- Department of Ultrasound Medicine, Yanbian University Hospital, Yanji, 133000, P. R. China.
- Department of Pathology and Cancer Research Center, Yanbian University Medical College, Gong Yuan Road No. 977, Yanji, 133002, P. R. China.
- Key Laboratory of the Science and Technology Department of Jilin Province, Yanji, P. R. China.
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12
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Zhang J, Li C, Dionigi G, Sun H. Tumor-Infiltrating Lymphocytes as Mediators of the Obesity and Papillary Thyroid Carcinoma Lymph Node Metastasis Association: An Observational Retrospective Cohort Study. Ann Surg Oncol 2025; 32:2353-2371. [PMID: 39658714 DOI: 10.1245/s10434-024-16647-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 11/21/2024] [Indexed: 12/12/2024]
Abstract
BACKGROUND Obesity increases the risk of papillary thyroid carcinoma (PTC) and lymph node metastasis (LNM), possibly via modulation of the tumor immunological microenvironment. MATERIALS AND METHODS The STROCSS guideline was followed to conduct a retrospective cohort study. Binary logistic regression analysis with odds ratios (OR) was performed to assess the association between tumor-infiltrating lymphocytes (TILs), obesity, and LNM. Using The Cancer Genome Atlas (TCGA) data, we examined the relationship between immune cell subsets and obesity-regulating molecules in thyroid cancer tissues. The Cox regression risk model was used to analyze the prognosis of thyroid cancer. RESULTS After adjusting for confounding factors, our findings revealed that overweight and obesity were associated with a decrease in TIL infiltration (OR 0.876, p = 0.005 and OR 0.795, p = 0.001, respectively). Furthermore, these conditions were observed to be correlated with increased likelihood of LNM (OR 1.134, p = 0.005 and OR 1.307, p < 0.001, respectively). On the contrary, TIL infiltration was inversely associated with LNM (OR 0.868, p < 0.001). When controlling for TIL infiltration as the sole variable, the combination of obesity and TIL infiltration did not independently predict LNM (adjusted OR 1.442, p = 0.113). However, obesity alone was found to elevate the likelihood of LNM (adjusted OR 1.539, p = 0.02). Additionally, adiponectin (a crucial adipokine) was reduced in obesity and demonstrated a negative correlation with the abundance of infiltrated dendritic cells and regulatory T cells, as evidenced by TCGA data analysis. Furthermore, ADIPOR2 expression negatively correlated with LNM and positively associated with unfavorable prognosis in PTC, with a hazard ratio of 0.480 (p = 0.007). CONCLUSIONS TIL infiltration may affect obesity-associated PTC LNM. Obesity may affect LNM and result in poor prognosis through ADIPOR2 regulation of antitumor immune cells.
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Affiliation(s)
- Jiao Zhang
- Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Jilin Provincial Engineering Laboratory of Thyroid Disease Prevention and Control, Changchun City, Jilin Province, China
| | - Changlin Li
- Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Jilin Provincial Engineering Laboratory of Thyroid Disease Prevention and Control, Changchun City, Jilin Province, China
| | - Gianlorenzo Dionigi
- Division of Surgery, Istituto Auxologico Italiano IRCCS, Milan, Italy
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Hui Sun
- Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Jilin Provincial Engineering Laboratory of Thyroid Disease Prevention and Control, Changchun City, Jilin Province, China.
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Hennessy MA, Cimino-Mathews A, Carter JM, Kachergus JM, Ma Y, Leal JP, Solnes LB, Denbow R, Abramson VG, Carey LA, Rimawi M, Specht J, Storniolo AM, Valero V, Vaklavas C, Winer EP, Krop IE, Wolff AC, Wahl RL, Perez EA, Huang CY, Stearns V, Thompson EA, Connolly RM. Multiplex Spatial Proteomic Analysis of HER2-Positive Breast Tumors Reveals Unique Molecular and Immunologic Features Associated With Treatment Response. JCO Precis Oncol 2025; 9:e2400546. [PMID: 40179327 PMCID: PMC11968088 DOI: 10.1200/po-24-00546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 12/17/2024] [Accepted: 02/21/2025] [Indexed: 04/05/2025] Open
Abstract
PURPOSE Predictive biomarkers to better tailor therapy for patients with early-stage human epidermal growth factor 2 (HER2)-positive breast cancer are a priority. We hypothesized that HER2 and immune-based biomarkers would be predictive of pathologic complete response (pCR) to preoperative trastuzumab/pertuzumab (HP). MATERIALS AND METHODS Patients with stage II/III, estrogen receptor (ER)-negative, HER2-positive breast cancer received neoadjuvant HP in the TBCRC026 clinical trial. The pCR after receiving HP alone was 22% (18/83). Tumor biopsies were performed at baseline. Secondary correlative objectives were to determine the relationship between HER2-based biomarkers and immune processes with pCR. NanoString code sets BC360 and IO360 were used to compare differential gene expression in baseline tumors that underwent pCR versus no pCR. NanoString GeoMx digital spatial profiling was used to assess immune protein abundance in intraepithelial and stromal segments. Stromal tumor-infiltrating lymphocytes and Ki67 were evaluated by hematoxylin and eosin and immunohistochemistry, respectively. RESULTS Intraepithelial HER2 protein abundance was significantly associated with pCR (P = .001). Low HER2 abundance tumors were primarily basal-like, and essentially all (19/20) failed to achieve pCR. High HER2 abundance tumors that achieved pCR (14/51) exhibited a high degree of immune cell activity, whereas high HER2 abundance tumors that failed to achieve pCR tumors (37/51) were enriched for M-phase processes and epidermal growth factor receptor signaling. Baseline Ki67 was significantly higher in nonresponders (P = .04). CONCLUSION ER-negative, HER2-positive breast cancer has unique molecular and immunologic features that may predict pCR after neoadjuvant HP. Validation of these potential biomarkers and composite biomarker analyses may guide design of future clinical trials.
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Affiliation(s)
| | - Ashley Cimino-Mathews
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
| | - Jodi M. Carter
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada
| | | | - Yaohua Ma
- Department of Quantitative Health Science, Mayo Clinic Florida, Jacksonville, FL
| | - Jeffrey P. Leal
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
| | - Lilja B. Solnes
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
| | - Rita Denbow
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
| | | | | | | | | | - Anna Maria Storniolo
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, IN
| | - Vicente Valero
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | | | | | - Antonio C. Wolff
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
| | | | - Edith A. Perez
- Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, FL
| | - Chiung-Yu Huang
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
- University of California, San Francisco, CA
| | - Vered Stearns
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
| | | | - Roisin M. Connolly
- Cancer Research @UCC, University College Cork, Cork, Ireland
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
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14
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Ni X, Wang W, Sun H, An R, Lei Y, Wang CL. A new marker for predicting sentinel lymph node metastasis in early (cT1-2N0) breast cancer: Tumor-infiltrating lymphocytes (TILs). PLoS One 2025; 20:e0320487. [PMID: 40106761 PMCID: PMC11922523 DOI: 10.1371/journal.pone.0320487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Accepted: 02/19/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Tumor-infiltrating lymphocytes (TILs) are associated with lymph node metastasis and prognosis in breast cancer. Therefore, we explored the value of TILs in predicting sentinel lymph node metastasis (SLNM) in patients with early-stage (cT1-2N0) breast cancer and provided a new method for preoperative assessment of SLNM status. METHODS This study included 337 patients with early-stage breast cancer who underwent surgery at our hospital from January 2022 to December 2023. The expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 in the patients was assessed using immunohistochemistry (IHC). TILs in the core needle biopsy samples were evaluated histopathologically, and patients were divided into high and low TILs groups based on the density of TILs. Statistical analysis was conducted, and a predictive model was established. RESULTS The study found that patients with high TILs had a significantly lower rate of SLNM compared to those with low TILs (P < 0.001). The cT stage and the level of TILs were identified as independent predictive factors for SLNM. The ROC curve analysis indicated that the density of TILs has good predictive efficacy for SLNM. Based on the results of the multivariate regression analysis, a nomogram predictive model for SLNM was constructed. CONCLUSIONS Our study showed that the density of TILs and cT stage are independent predictive factors for SLNM in early-stage (cT1-2N0) breast cancer, and the predictive effect of TILs density on SLNM is significant in Luminal and triple-negative breast cancers.
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Affiliation(s)
- Xihao Ni
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong Province, People’s Republic of China,
| | - Weitao Wang
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong Province, People’s Republic of China,
| | - Huimin Sun
- Department of Pathology, Weifang People’s Hospital, Weifang, Shandong Province, People’s Republic of China,
| | - Ran An
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong Province, People’s Republic of China,
| | - Ying Lei
- Department of Breast Surgery, Weifang People’s Hospital, Weifang, Shandong Province, People’s Republic of China
| | - Chang-liang Wang
- Department of Breast Surgery, Weifang People’s Hospital, Weifang, Shandong Province, People’s Republic of China
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15
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Lan M, Qin S, Wei J, Wu L, Lu Z, Huang W. The SLC26A4-AS1/NTRK2 axis in breast cancer: insights into the ceRNA network and implications for prognosis and immune microenvironment. Discov Oncol 2025; 16:329. [PMID: 40090984 PMCID: PMC11911282 DOI: 10.1007/s12672-025-02080-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 03/05/2025] [Indexed: 03/19/2025] Open
Abstract
Breast cancer is a leading malignancy in women, with mortality disparities between developed and underdeveloped regions. Accumulating evidence suggests that the competitive endogenous RNA (ceRNA) regulatory networks play paramount roles in various human cancers. However, the complexity and behavior characteristics of the ceRNA network in breast cancer progression have not been fully elucidated. The expression profiles of three RNAs (long non-coding RNAs [lncRNAs], microRNAs [miRNAs], and mRNAs) were extracted from breast cancer and adjacent samples were sourced from the TCGA database. The SLC26A4-AS1- hsa-miR-19a-3p-NTRK2 ceRNA network related to the prognosis of breast cancer was obtained by performing bioinformatics analysis. Importantly, we identified the SLC26A4-AS1/NTRK2 axis within the ceRNA network through correlation analysis and found it to be a potential prognostic model in clinical outcomes based on Cox regression analysis. Moreover, methylation analysis suggests that the aberrant downregulation of the SLC26A4-AS1/NTRK2 axis might be attributed to hypermethylation at specific sites. Immune infiltration analysis indicates that the SLC26A4-AS1/NTRK2 axis may have implications for the alteration of the tumor immune microenvironment and the emergence and progression of immune evasion in breast cancer. Finally, we validated the expression of SLC26A4-AS1-hsa-miR-19a-3p-NTRK2 in breast cancer cell lines. In summary, the present study posits that the SLC26A4-AS1/NTRK2 axis, based on the ceRNA network, could be a novel and significant prognostic factor associated with breast cancer diagnosis and outcomes.
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Affiliation(s)
- Mengqiu Lan
- Liuzhou Municipal Liutie Central Hospital, Liuzhou, 545007, Guangxi, China
| | - Shuang Qin
- Liuzhou Municipal Liutie Central Hospital, Liuzhou, 545007, Guangxi, China
| | - Jingjing Wei
- Liuzhou Municipal Liutie Central Hospital, Liuzhou, 545007, Guangxi, China
| | - Lihong Wu
- Liuzhou Municipal Liutie Central Hospital, Liuzhou, 545007, Guangxi, China
| | - Zhenni Lu
- Liuzhou Municipal Liutie Central Hospital, Liuzhou, 545007, Guangxi, China
| | - Wenjie Huang
- Department of Reproductive Medicine, Guangzhou Women and Children'S Medical Center Liuzhou Hospital, Liuzhou, 545616, Guangxi, China.
- Department of Reproductive Medicine, Liuzhou Maternity and Child Healthcare Hospital, Liuzhou, 545001, Guangxi, China.
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16
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Jin L, Yang Z, Tang W, Yu P, Chen R, Xu Y, Zhang J. The evolving landscape of genetic biomarkers for immunotherapy in primary and metastatic breast cancer. Front Oncol 2025; 15:1522262. [PMID: 40182039 PMCID: PMC11966456 DOI: 10.3389/fonc.2025.1522262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 01/30/2025] [Indexed: 04/05/2025] Open
Abstract
Background Major advances have been achieved in the characterization of primary breast cancer genomic profiles. Limited information is available on the genomic profile of tumors originating from different metastatic locations in recurrent/metastatic (R/M) breast cancer, especially in Asian patients. This study aims to decipher the mutational profiles of primary and R/M breast cancer in Chinese patients using next-generation sequencing. Methods A total of 563 breast cancer patients were enrolled, and 590 tumor tissues and matched peripheral blood samples were collected and subjected to targeted sequencing with a panel of 1,021 cancer-related genes. The mutation spectrum, DNA damage response (DDR) genes, commonly altered signal pathways, and immunotherapy-related markers were compared between primary and R/M breast cancer. The molecular differences between our cohort and the Memorial Sloan Kettering Cancer Center (MSKCC) dataset were also explored. Results A total of 361 samples from primary and 229 samples from R/M breast cancer were analyzed. BRCA2, ATRX, and ATM were more frequently observed in R/M lesions among the 36 DDR genes. An ESR1 mutation and PD-L1 and PD-L2 amplification were enriched in R/M breast cancer (all p<0.05). Compared with the MSKCC dataset, we recruited more patients diagnosed at age 50 or younger and more patients with triple-negative breast cancer (TNBC) subtypes. The TNBC patients in our dataset had a higher percentage of PD-L1 amplification in metastasis tumors (p<0.05). Conclusions This study revealed the distinctive mutational features of primary and R/M tumors in Chinese breast cancer patients, which are different from those from Western countries. The enrichment of PD-L1 amplification in metastatic TNBC indicates the necessity to re-biopsy metastatic tumors for immunotherapy.
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Affiliation(s)
- Liang Jin
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zijian Yang
- Department of Breast and Thyroid Surgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Wei Tang
- Department of Breast Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Pengli Yu
- Medical Department, Geneplus-Beijing, Beijing, China
| | - Rongrong Chen
- Medical Department, Geneplus-Beijing, Beijing, China
| | - Yan Xu
- Department of Breast and Thyroid Surgery, Daping Hospital, Army Military Medical University, Chongqing, China
| | - Jun Zhang
- Department of Thyroid and Breast Surgery, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, China
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Nagahashi M, Ishikawa E, Nagai T, Kanaoka H, Oshiro A, Togashi Y, Hattori A, Tsuchida J, Higuchi T, Nishimukai A, Murase K, Takatsuka Y, Kihara T, Ling Y, Okuda S, Hirota S, Miyoshi Y. Clinical utility of tumor-infiltrating lymphocyte evaluation by two different methods in breast cancer patients treated with neoadjuvant chemotherapy. Breast Cancer 2025; 32:404-415. [PMID: 39808396 PMCID: PMC11842476 DOI: 10.1007/s12282-025-01665-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 01/05/2025] [Indexed: 01/16/2025]
Abstract
PURPOSE The aim of this study was to examine the clinical utility of tumor-infiltrating lymphocytes (TILs) evaluated by "average" and "hot-spot" methods in breast cancer patients. METHODS We examined 367 breast cancer patients without neoadjuvant chemotherapy (NAC) by average and hot-spot methods to determine the consistency of TIL scores between biopsy and surgical specimens. TIL scores before NAC were also compared with the pathological complete response (pCR) rate and clinical outcomes in 144 breast cancer patients that received NAC. TIL scores evaluated by the two methods were predicted from clinicopathological data using random forest regression. RESULTS Surgical specimens showed higher TIL scores than biopsy specimens using the hot-spot method (p < 0.001), while biopsy and surgical specimens showed similar TIL scores using the average method. There was a linear relationship between the pCR rate and TIL scores determined using hot-spot (p < 0.001) and average methods (p = 0.001). Patients without pCR and low TILs by the average method had significantly worse overall survival compared to other patients (p = 0.02). The root mean squared errors of the predicted TIL score for the test set were 19.662 (hot-spot) and 10.955 (average). CONCLUSION The average method may have an advantage for breast cancer patients receiving NAC, since the TIL score using this method is more consistent between biopsy and surgical specimens, and it associates better with clinical outcomes. Our exploratory study showed that machine learning from clinicopathological data may better predict TIL scores assessed by the average, rather than hot-spot, method.
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Affiliation(s)
- Masayuki Nagahashi
- Division of Breast and Endocrine Surgery, Department of Surgery, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
| | - Eri Ishikawa
- Department of Diagnostic Pathology, School of Medicine, Hyogo Medical University, Nishinomiya City, Hyogo, Japan
| | - Takahiro Nagai
- Center for Genomic Data Management, Niigata University Medical and Dental Hospital, 1-754 Asahimachi-dori, Chuo-ku, Niigata, 951-8520, Japan
| | - Haruka Kanaoka
- Division of Breast and Endocrine Surgery, Department of Surgery, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Aoi Oshiro
- Division of Breast and Endocrine Surgery, Department of Surgery, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Yusa Togashi
- Division of Breast and Endocrine Surgery, Department of Surgery, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Akira Hattori
- Division of Breast and Endocrine Surgery, Department of Surgery, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Junko Tsuchida
- Division of Breast and Endocrine Surgery, Department of Surgery, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Tomoko Higuchi
- Division of Breast and Endocrine Surgery, Department of Surgery, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Arisa Nishimukai
- Division of Breast and Endocrine Surgery, Department of Surgery, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Keiko Murase
- Division of Breast and Endocrine Surgery, Department of Surgery, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Yuichi Takatsuka
- Division of Breast and Endocrine Surgery, Department of Surgery, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Takako Kihara
- Department of Diagnostic Pathology, School of Medicine, Hyogo Medical University, Nishinomiya City, Hyogo, Japan
| | - Yiwei Ling
- Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, 2-5274 Gakkocho-dori, Chuo-ku, Niigata, 951-8514, Japan
- Medical AI Center, Niigata University School of Medicine, 2-5274 Gakkocho-dori, Chuo-ku, Niigata, 951-8514, Japan
| | - Shujiro Okuda
- Center for Genomic Data Management, Niigata University Medical and Dental Hospital, 1-754 Asahimachi-dori, Chuo-ku, Niigata, 951-8520, Japan
- Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, 2-5274 Gakkocho-dori, Chuo-ku, Niigata, 951-8514, Japan
- Medical AI Center, Niigata University School of Medicine, 2-5274 Gakkocho-dori, Chuo-ku, Niigata, 951-8514, Japan
| | - Seiichi Hirota
- Department of Diagnostic Pathology, School of Medicine, Hyogo Medical University, Nishinomiya City, Hyogo, Japan
| | - Yasuo Miyoshi
- Division of Breast and Endocrine Surgery, Department of Surgery, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
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Kaewkedsri P, Intarawichian P, Jessadapattarakul S, Kunprom W, Koonmee S, Thanee M, Somintara O, Wongbuddha A, Chadbunchachai P, Nawapun S, Aphivatanasiri C. Programmed Cell Death Ligand 1 (PD-L1) and Major Histocompatibility Complex Class I (MHC Class I) Expression Patterns and Their Pathologic Associations in Triple-Negative Breast Cancer. BREAST CANCER (DOVE MEDICAL PRESS) 2025; 17:123-143. [PMID: 39936074 PMCID: PMC11812676 DOI: 10.2147/bctt.s506833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Accepted: 01/24/2025] [Indexed: 02/13/2025]
Abstract
Purpose This study aims to investigate the clinicopathological characteristics of triple-negative breast cancer (TNBC) in relation to programmed cell death ligand 1 (PD-L1) and major histocompatibility complex class I (MHC class I) expression, with a focus on their prognostic significance. Patients and Methods A retrospective analysis was conducted on formalin-fixed paraffin-embedded (FFPE) tissue samples from 148 TNBC patients diagnosed between 2008 and 2021. Immunohistochemical analysis evaluated PD-L1 and MHC class I expression. PD-L1 was assessed using Combine Positive Scores (CPS), with the threshold set at CPS ≥ 1 and CPS ≥ 10. MHC class I expression was categorized into low and high levels. Associations between these markers, clinicopathological features, overall survival (OS), and disease-free survival (DFS) were analyzed. PD-L1 expression was also compared between older FFPE blocks (2008-2018) versus newer blocks (2019-2021). Results PD-L1 expression was observed in 29.1% of cases with a Combined Positive Score (CPS) ≥1 and 8.8% of CPS ≥10 cases. MHC class I expression was evenly split between low and high levels. Older FFPE blocks (2008-2018) showed lower PD-L1 expression than newer blocks (2019-2021). There was no significant association between PD-L1 expression and overall survival (OS) or disease-free survival (DFS). However, high MHC class I expression was strongly associated with improved OS (HR = 0.469, 95% CI: 0.282-0.780, p=0.004). Patients with negative PD-L1 and high MHC class I expression had the most favorable prognosis, with significant OS for CPS ≥1 (HR = 0.447, 95% CI: 0.236-0.846, p=0.013) and CPS ≥10 (HR = 0.516, 95% CI: 0.307-0.869, p=0.013). Conclusion These findings support the potential of PD-L1 and MHC class I expression as prognostic markers for TNBC, offering insights to guide treatment decisions and improve patient outcomes.
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Affiliation(s)
- Ponkrit Kaewkedsri
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | | | | | - Waritta Kunprom
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Supinda Koonmee
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Malinee Thanee
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Ongart Somintara
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Anongporn Wongbuddha
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Payia Chadbunchachai
- Department of Radiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Supajit Nawapun
- Department of Radiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
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19
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Han HS, Aldrich AL, Garg SK, Weinfurtner RJ, Nguyen JV, Mo Q, Whiting J, Childress J, Soliman H, Costa R, Armaghani A, Soyano A, Kiluk J, Hoover S, Lee MC, Khakpour N, Shenoi N, Jameel Z, Koski GK, Czerniecki BJ. Alteration of the Tumor Microenvironment With Intratumoral Dendritic Cells Before Chemotherapy in ERBB2 Breast Cancer: A Nonrandomized Clinical Trial. JAMA Oncol 2025; 11:119-127. [PMID: 39636623 PMCID: PMC11622104 DOI: 10.1001/jamaoncol.2024.5371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 09/12/2024] [Indexed: 12/07/2024]
Abstract
Importance Current chemotherapy regimens for patients with ERBB2 (formerly HER2)-positive breast cancer are associated with considerable morbidity. These patients may benefit from more effective and less toxic therapies. Objective To evaluate the safety, immunogenicity, and preliminary efficacy of intratumoral (IT) delivery of conventional type 1 dendritic cells (cDC1) in combination with ERBB2-targeted therapies. Design, Setting, and Participants This phase 1 (lead-in phase of a single-center phase 2 trial) nonrandomized clinical trial was conducted at Moffitt Cancer Center (Tampa, Florida). Patients were enrolled from October 2021 to October 2022. Data were analyzed in 2023 Patients with early-stage ERBB2-positive breast cancer with tumors 1 cm or larger were eligible. Interventions Treatment included IT delivery of cDC1, 6 times weekly, followed by paclitaxel, 80 mg/m2, intravenously, 12 times weekly. Trastuzumab (8 mg/kg loading dose, then 6 mg/kg) and pertuzumab (840 mg loading dose, then 420 mg) were administered intravenously every 3 weeks for 6 cycles starting from day 1 of cDC1 injections. Two dose levels (DLs) of IT cDC1 (DL1 = 50 million and DL2 = 100 million cells) were evaluated, including 6 patients in each DL. Main Outcomes and Measures The primary outcomes were the safety and immune response, and the secondary outcomes were the antitumor efficacy as measured by breast magnetic resonance imaging and residual cancer burden at surgery following neoadjuvant therapy. Results Twelve ERBB2-positive patients were enrolled and received treatment (DL1 = 6 and DL2 = 6). Nine patients had hormone receptor-positive disease and 3 had hormone receptor-negative disease, with clinical stage I (n = 5), II (n = 4), and III (n = 3). The most frequently observed adverse events with cDC1 were grade 1 to 2 chills (50%), fatigue (41.7%), headache (33%), and injection site reactions (33%). DL2 was associated with a diminished anti-ERBB2 CD4 T-helper 1 blood response with a concomitant increase in innate and adaptive responses within the tumor. Preimmunotherapy and postimmunotherapy breast magnetic resonance imaging results showed 9 objective responses, 6 partial responses, 3 complete responses, and 3 stable diseases. Following surgery, 7 patients had a pathologic complete response. Conclusions and Relevance In this nonrandomized clinical trial, the addition of IT cDC1 and trastuzumab/pertuzumab before neoadjuvant chemotherapy was well tolerated with manageable adverse effects. Based on safety and immunogenicity, DL2 was selected for the phase 2 dose. Trial Registration ClinicalTrials.gov Identifier: NCT05325632.
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Affiliation(s)
- Hyo S. Han
- Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Amy L. Aldrich
- Clinical Science Division, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Saurabh K. Garg
- Clinical Science Division, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - R. Jared Weinfurtner
- Diagnostic Imaging, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Jonathan V. Nguyen
- Advanced Analytical and Digital Laboratory, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Qianxing Mo
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Junmin Whiting
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Jennifer Childress
- Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Hatem Soliman
- Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Ricardo Costa
- Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Avan Armaghani
- Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Aixa Soyano
- Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - John Kiluk
- Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Susan Hoover
- Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Marie C. Lee
- Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Nazanin Khakpour
- Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Nithin Shenoi
- Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Zena Jameel
- Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Gary K. Koski
- Department of Biological Sciences, Kent State University, Kent, Ohio
| | - Brian J. Czerniecki
- Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
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20
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Liu S, Yin N, Zhao Y, Yan B, Li S, Gao S. A highly sensitive electrochemical aptasensor for detecting broad-spectrum estrogen molecules in clinical samples. Talanta 2025; 283:127071. [PMID: 39447399 DOI: 10.1016/j.talanta.2024.127071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 09/26/2024] [Accepted: 10/16/2024] [Indexed: 10/26/2024]
Abstract
The lack of sensitive and accurate monitoring methods for in vivo estrogen levels presents challenges for better prevention of estrogen-induced diseases. We have developed a label-free electrochemical aptasensor that demonstrates high sensitivity and selectivity for the broad-spectrum detection of estrogen molecules. This biosensor uses gold nanoparticles for electrochemical signal amplification and aptamers for broad-spectrum target recognition, enabling precise detection of trace amounts of estrogen in serum samples. The aptasensor demonstrates high sensitivity in estrogen detection, with a linear detection range of 0.01-1 nM and a minimum detection limit of 3 pM. It also exhibits excellent selectivity and interference resistance, with a detection error of less than 19 %, even in the presence of high concentrations of other biological substances. Additionally, molecular dynamics simulations were performed to provide insights into the molecular mechanism of aptamer broad-spectrum recognition and construction principles underlying the sensor. We anticipate that this aptasensor will serve as a robust, convenient, and cost-effective detection method, offering a valuable solution for the prevention of estrogen-induced diseases.
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Affiliation(s)
- Siyao Liu
- School of Medicine, Shanghai University, Shanghai, 200444, China
| | - Ning Yin
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, 200080, China
| | - Ya Zhao
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, 200080, China
| | - Biao Yan
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, 200080, China.
| | - Shengjie Li
- Department of Clinical Laboratory, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, 200031, China.
| | - Shunxiang Gao
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, 200080, China.
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21
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Li R, Bing X, Su X, Zhang C, Sun H, Dai Z, Ouyang A. The potential value of dual-energy CT radiomics in evaluating CD8 +, CD163 + and αSMA + cells in the tumor microenvironment of clear cell renal cell carcinoma. Clin Transl Oncol 2025; 27:716-726. [PMID: 39083142 DOI: 10.1007/s12094-024-03637-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 07/19/2024] [Indexed: 02/01/2025]
Abstract
PURPOSE This study aims to develop radiomics models and a nomogram based on machine learning techniques, preoperative dual-energy computed tomography (DECT) images, clinical and pathological characteristics, to explore the tumor microenvironment (TME) of clear cell renal cell carcinoma (ccRCC). METHODS We retrospectively recruited of 87 patients diagnosed with ccRCC through pathological confirmation from Center I (training set, n = 69; validation set, n = 18), and collected their DECT images and clinical information. Feature selection was conducted using variance threshold, SelectKBest, and the least absolute shrinkage and selection operator (LASSO). Radiomics models were then established using 14 classifiers to predict TME cells. Subsequently, we selected the most predictive radiomics features to calculate the radiomics score (Radscore). A combined model was constructed through multivariate logistic regression analysis combining the Radscore and relevant clinical characteristics, and presented in the form of a nomogram. Additionally, 17 patients were recruited from Center II as an external validation cohort for the nomogram. The performance of the models was assessed using methods such as the area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA). RESULTS The validation set AUC values for the radiomics models assessing CD8+, CD163+, and αSMA+ cells were 0.875, 0.889, and 0.864, respectively. Additionally, the external validation cohort AUC value for the nomogram reaches 0.849 and shows good calibration. CONCLUSION Radiomics models could allow for non-invasive assessment of TME cells from DECT images in ccRCC patients, promising to enhance our understanding and management of the tumor.
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MESH Headings
- Humans
- Carcinoma, Renal Cell/diagnostic imaging
- Carcinoma, Renal Cell/pathology
- Carcinoma, Renal Cell/immunology
- Kidney Neoplasms/diagnostic imaging
- Kidney Neoplasms/pathology
- Kidney Neoplasms/immunology
- Male
- Female
- Tumor Microenvironment/immunology
- Middle Aged
- Retrospective Studies
- Tomography, X-Ray Computed/methods
- Nomograms
- Aged
- CD163 Antigen
- Antigens, CD/analysis
- Antigens, Differentiation, Myelomonocytic/analysis
- Antigens, Differentiation, Myelomonocytic/metabolism
- Receptors, Cell Surface/analysis
- Adult
- Machine Learning
- Radiomics
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Affiliation(s)
- Ruobing Li
- Department of Radiology, Central Hospital Affiliated to Shandong First Medical University, 105 JieFang Road, Jinan, 250013, China
- Shandong First Medical University, Jinan, 250117, China
| | - Xue Bing
- Department of Radiology, Central Hospital Affiliated to Shandong First Medical University, 105 JieFang Road, Jinan, 250013, China
| | - Xinyou Su
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, China
| | - Chunling Zhang
- Department of Radiology, Central Hospital Affiliated to Shandong First Medical University, 105 JieFang Road, Jinan, 250013, China
| | - Haitao Sun
- Department of Radiology, Central Hospital Affiliated to Shandong First Medical University, 105 JieFang Road, Jinan, 250013, China
| | - Zhengjun Dai
- Scientific Research Department, Huiying Medical Technology Co, Ltd, Beijing, 100192, China
| | - Aimei Ouyang
- Department of Radiology, Central Hospital Affiliated to Shandong First Medical University, 105 JieFang Road, Jinan, 250013, China.
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22
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Chen IC, Lin CH, Chang DY, Wei-Wu Chen T, Wang MY, Ma WL, Lin YT, Huang SM, Hsu CL, Lu YS. Hormone therapy enhances anti-PD1 efficacy in premenopausal estrogen receptor-positive and HER2-negative advanced breast cancer. Cell Rep Med 2025; 6:101879. [PMID: 39730000 PMCID: PMC11866513 DOI: 10.1016/j.xcrm.2024.101879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 09/19/2024] [Accepted: 11/26/2024] [Indexed: 12/29/2024]
Abstract
The efficacy of immunotherapy for estrogen receptor-positive/HER2-negative (ER+/HER2-) metastatic breast cancer (MBC) has not been proven. We conduct a phase 1b/2 trial to assess the efficacy of combining pembrolizumab (anti-PD1 antibody), exemestane (nonsteroidal aromatase inhibitor), and leuprolide (gonadotropin-releasing hormone agonist) for 15 patients with premenopausal ER+/HER2- MBC who had failed one to two lines of hormone therapy (HT) without chemotherapy. The primary endpoint of progression-free survival rate at 8 months (i.e., 64.3%) is achieved. Moreover, 5 of the 14 evaluable subjects exhibited partial responses (overall response rate = 35.7%). The combination of anti-PD1 antibody and anti-hormone therapy is associated with an enhanced immunoreactive microenvironment influencing treatment efficacy, as observed in pre- and post-treatment tumor samples through NanoString analysis. Post-treatment tumors are associated with increased immune response and immune cells. The findings indicate that combining HT with anti-PD1 antibody is a promising treatment strategy for patients with premenopausal ER+/HER2- MBC. This study was registered at ClinicalTrials.gov (NCT02990845).
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Affiliation(s)
- I-Chun Chen
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei City 106, Taiwan; Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei City 100, Taiwan; Department of Oncology, National Taiwan University Hospital, Taipei City 100, Taiwan
| | - Ching-Hung Lin
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei City 106, Taiwan; Department of Oncology, National Taiwan University Hospital, Taipei City 100, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei City 100, Taiwan
| | - Dwan-Ying Chang
- Department of Oncology, National Taiwan University Hospital, Taipei City 100, Taiwan
| | - Tom Wei-Wu Chen
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei City 106, Taiwan; Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei City 100, Taiwan; Department of Oncology, National Taiwan University Hospital, Taipei City 100, Taiwan
| | - Ming-Yang Wang
- Department of Surgical Oncology, National Taiwan University Cancer Center, Taipei City 106, Taiwan; Department of Surgery, National Taiwan University Hospital, Taipei City 100, Taiwan
| | - Wei-Li Ma
- Department of Oncology, National Taiwan University Hospital, Taipei City 100, Taiwan
| | - Yi-Ting Lin
- Department of Oncology, National Taiwan University Hospital, Taipei City 100, Taiwan
| | - Shu-Min Huang
- Department of Oncology, National Taiwan University Hospital, Taipei City 100, Taiwan
| | - Chia-Lang Hsu
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei City 100, Taiwan; Department of Medical Research, National Taiwan University Hospital, Taipei City 100, Taiwan
| | - Yen-Shen Lu
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei City 106, Taiwan; Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei City 100, Taiwan; Department of Oncology, National Taiwan University Hospital, Taipei City 100, Taiwan.
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23
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Toney NJ, Opdenaker LM, Frerichs L, Modarai SR, Ma A, Archinal H, Ajayi GO, Sims-Mourtada J. B cells enhance IL-1 beta driven invasiveness in triple negative breast cancer. Sci Rep 2025; 15:2211. [PMID: 39820772 PMCID: PMC11739487 DOI: 10.1038/s41598-025-86064-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 01/08/2025] [Indexed: 01/19/2025] Open
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype often characterized by high lymphocyte infiltration, including tumor-infiltrating B cells (TIBs). These cells are present even in early stages of TNBC and associated with microinvasion. This study shows that co-culturing TNBC cells with B cells increases Interleukin-1β (IL-1β) expression and secretion. We further show that B cell-induced IL-1β activates NFκB signaling, leading to higher expression of target genes and promoting IL-1β-dependent increases in matrix metalloproteinase (MMP) activity, invasion, and migration. Immunohistochemical analysis of IL-1β and TIBs in triple-negative ductal carcinoma in situ (DCIS, n = 90) and invasive TNBC (n = 171) revealed that in DCIS, TIBs correlated with IL-1β expression and microinvasion, with IL-1β also linked to recurrence. In invasive TNBC, IL-1β expression correlated with TIB density and stage, with high IL-1β levels associated with poorer survival outcomes. These findings suggest that early B cell presence in TNBC can induce IL-1β secretion, enhancing invasion and mobility through IL-1β-NFκB signaling. This highlights the potential of IL-1 inhibitors as preventive and therapeutic options for hormone receptor-negative DCIS and TNBC.
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MESH Headings
- Humans
- Triple Negative Breast Neoplasms/pathology
- Triple Negative Breast Neoplasms/metabolism
- Triple Negative Breast Neoplasms/immunology
- Interleukin-1beta/metabolism
- Interleukin-1beta/genetics
- Female
- Neoplasm Invasiveness
- B-Lymphocytes/immunology
- B-Lymphocytes/metabolism
- B-Lymphocytes/pathology
- Cell Line, Tumor
- NF-kappa B/metabolism
- Signal Transduction
- Gene Expression Regulation, Neoplastic
- Cell Movement
- Middle Aged
- Coculture Techniques
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/metabolism
- Lymphocytes, Tumor-Infiltrating/pathology
- Carcinoma, Intraductal, Noninfiltrating/pathology
- Carcinoma, Intraductal, Noninfiltrating/metabolism
- Carcinoma, Intraductal, Noninfiltrating/immunology
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Affiliation(s)
- Nicole J Toney
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute Christiana Care Health Services, Inc., 4701 Ogletown Stanton Rd Suite 4300, Newark, DE, 19713, USA
- Department of Biological Sciences, The University of Delaware, Newark, DE, USA
| | - Lynn M Opdenaker
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute Christiana Care Health Services, Inc., 4701 Ogletown Stanton Rd Suite 4300, Newark, DE, 19713, USA
| | - Lisa Frerichs
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute Christiana Care Health Services, Inc., 4701 Ogletown Stanton Rd Suite 4300, Newark, DE, 19713, USA
| | - Shirin R Modarai
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute Christiana Care Health Services, Inc., 4701 Ogletown Stanton Rd Suite 4300, Newark, DE, 19713, USA
| | - Aihui Ma
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute Christiana Care Health Services, Inc., 4701 Ogletown Stanton Rd Suite 4300, Newark, DE, 19713, USA
| | - Holly Archinal
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute Christiana Care Health Services, Inc., 4701 Ogletown Stanton Rd Suite 4300, Newark, DE, 19713, USA
| | - Grace O Ajayi
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute Christiana Care Health Services, Inc., 4701 Ogletown Stanton Rd Suite 4300, Newark, DE, 19713, USA
- Department of Biological Sciences, The University of Delaware, Newark, DE, USA
| | - Jennifer Sims-Mourtada
- Cawley Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute Christiana Care Health Services, Inc., 4701 Ogletown Stanton Rd Suite 4300, Newark, DE, 19713, USA.
- Department of Biological Sciences, The University of Delaware, Newark, DE, USA.
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24
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Shaitelman SF, Le-Petross H, Raso MG, Swanson DM, Schalck AP, Contreras A, Yang F, Muruganandham M, Zhao GZ, Sawakuchi GO, Kim LH, Batra H, Smith BD, Stauder MC, Woodward WA, Reddy JP, Litton JK, Thompson A, Bedrosian I, Mittendorf EA. PRECISE: Preoperative Radiation Therapy to Elicit Critical Immune Stimulating Effects-A Phase 2 Clinical Trial. Int J Radiat Oncol Biol Phys 2025; 121:90-96. [PMID: 39147206 DOI: 10.1016/j.ijrobp.2024.08.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 07/23/2024] [Accepted: 08/02/2024] [Indexed: 08/17/2024]
Abstract
PURPOSE Radiation therapy is an underinvestigated tool for priming the immune system in intact human breast cancers. We sought here to investigate if a preoperative radiation therapy boost delivered was associated with a significant change in tumor-infiltrating lymphocytes (TILs) in the tumor in estrogen receptor positive, HER2Neu nonamplified breast cancers. METHODS AND MATERIALS A total of 20 patients were enrolled in a phase 2 clinical trial and received either 7.5 Gy × 1 fraction or 2 Gy × 5 fractions, completed 6 to 8 days before surgery. Percent stromal TILs were evaluated on hematoxylin and eosin-stained samples. Short-term safety was assessed based on time to surgery, toxicities, and cosmesis up to 6 months after boost. RESULTS Stromal TIL increased 6 to 8 days after completion of boost radiation therapy (median 3.0 [IQR, 1.0-6.5]) before radiation therapy versus median 5.0 (IQR, 1.5-8.0) after radiation therapy, P = .0037. Zero grade ≥3 toxicities up to 6 months after boost were experienced. In all, 94% (16/17) patients with 6-month follow-up cosmetic assessment after breast conservation had good-excellent cosmesis by physician assessment. CONCLUSION In this phase 2 trial, preoperative radiation therapy boost resulted in a short-term increase in stromal TIL with minimal toxicities. Preoperative breast radiation therapy appears to be safe and may be a feasible means for priming the tumor microenvironment.
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Affiliation(s)
- Simona F Shaitelman
- Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Huong Le-Petross
- Department of Breast Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Maria G Raso
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - David M Swanson
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Aislyn P Schalck
- Department of Genomics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Alejandro Contreras
- Department of Anatomical Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Fei Yang
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Manickam Muruganandham
- Department of Radiation Physics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - George Z Zhao
- Department of Radiation Physics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Gabriel O Sawakuchi
- Department of Radiation Physics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Leonard H Kim
- Department of Radiation Oncology, MD Anderson Cancer Center at Cooper, Camden, New Jersey
| | - Harsh Batra
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Benjamin D Smith
- Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael C Stauder
- Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Wendy A Woodward
- Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jay P Reddy
- Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jennifer K Litton
- Department of Clinical Research, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Alastair Thompson
- Section of Breast Surgery, Division of Surgical Oncology, Baylor College of Medicine, Houston, Texas
| | - Isabelle Bedrosian
- Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Elizabeth A Mittendorf
- Division of Breast Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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25
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Ishikawa E, Watanabe T, Kihara T, Kuroiwa M, Komatsu M, Urano S, Nagahashi M, Hirota S, Miyoshi Y. The cytokine profile correlates with less tumor-infiltrating lymphocytes in luminal A breast cancer. Breast Cancer Res Treat 2025; 209:291-302. [PMID: 39402242 PMCID: PMC11785682 DOI: 10.1007/s10549-024-07492-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 09/05/2024] [Indexed: 02/02/2025]
Abstract
PURPOSE Tumor-infiltrating lymphocyte (TIL) levels are prognostic and predictive factors for breast cancer. Unlike other subtypes, most luminal A breast cancers are immune deserts; however, the underlying mechanisms are poorly understood. METHODS Immune-related cytokines, chemokines, and growth factors were measured in the sera of 103 patients with breast cancer using a multiplex panel. The TILs were evaluated for hotspot lesions. RESULTS Circulating interleukin 1 receptor antagonist (IL-1ra), IL-8, IL-12, IL-17, macrophage inflammatory protein-1β (MIP-1b), and platelet-derived growth factor B homodimer (PDGF-bb) concentrations were significantly associated with TIL levels. Cluster analysis using these six variables identified six clusters related to TIL levels. Breast cancers with high TILs (≥ 50%) were most frequent in cluster 3 (9 out of 15 cases, 60.0%), followed by cluster 1 (8 out of 34 cases, 23.5%), and the fewest in cluster 6 (1 out of 21 cases, 4.8%), whereas only one or three cases were present in clusters 2, 4, and 5 (p = 0.0064). Cluster 6, consisting mostly of luminal A (19 out of 21 cases, 90.5%), showed high levels of IL-12, IL-17, and PDGF-bb, and low levels of MIP-1b. CONCLUSION We identified a luminal A-associated immunosuppressive cytokine signature in circulation. These results suggest that a tumor microenvironment with high levels of IL-17 and PDGF-bb, and low levels of MIP-1b in luminal A breast cancers results in low induction of TILs. Our data may partially explain the low TIL levels observed in the patients with luminal A breast cancer.
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Affiliation(s)
- Eri Ishikawa
- Department of Surgical Pathology, School of Medicine, Hyogo Medical University, Nishinomiya City, Hyogo, Japan
| | - Takahiro Watanabe
- Department of Surgical Pathology, School of Medicine, Hyogo Medical University, Nishinomiya City, Hyogo, Japan
- Department of Clinical Pathology, Chibune General Hospital, Osaka, Japan
| | - Takako Kihara
- Department of Surgical Pathology, School of Medicine, Hyogo Medical University, Nishinomiya City, Hyogo, Japan
| | - Mamiko Kuroiwa
- Division of Breast and Endocrine Surgery, Department of Surgery, School of Medicine, Hyogo Medical University, Mukogawa-Cho 1-1, Nishinomiya City, Hyogo, 663-8501, Japan
| | - Miki Komatsu
- Division of Breast and Endocrine Surgery, Department of Surgery, School of Medicine, Hyogo Medical University, Mukogawa-Cho 1-1, Nishinomiya City, Hyogo, 663-8501, Japan
| | - Sayaka Urano
- Division of Breast and Endocrine Surgery, Department of Surgery, School of Medicine, Hyogo Medical University, Mukogawa-Cho 1-1, Nishinomiya City, Hyogo, 663-8501, Japan
| | - Masayuki Nagahashi
- Division of Breast and Endocrine Surgery, Department of Surgery, School of Medicine, Hyogo Medical University, Mukogawa-Cho 1-1, Nishinomiya City, Hyogo, 663-8501, Japan
| | - Seiichi Hirota
- Department of Surgical Pathology, School of Medicine, Hyogo Medical University, Nishinomiya City, Hyogo, Japan
| | - Yasuo Miyoshi
- Division of Breast and Endocrine Surgery, Department of Surgery, School of Medicine, Hyogo Medical University, Mukogawa-Cho 1-1, Nishinomiya City, Hyogo, 663-8501, Japan.
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Yamaguchi K, Nakazono T, Egashira R, Fukui S, Imaizumi T, Maruyama K, Nickel D, Hamamoto T, Yamaguchi R, Irie H. Relationship between kinetic parameters of ultrafast dynamic contrast-enhanced (DCE) MRI and tumor-infiltrating lymphocytes (TILs) in breast cancer. Jpn J Radiol 2025; 43:43-50. [PMID: 39186213 PMCID: PMC11717854 DOI: 10.1007/s11604-024-01645-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 08/15/2024] [Indexed: 08/27/2024]
Abstract
PURPOSE To evaluate the relationship between kinetic parameters of ultrafast dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and tumor-infiltrating lymphocytes (TILs) in breast cancer. PATIENTS AND METHODS This retrospective study was approved by an institutional review board and included 76 women (median age: 60) with 76 surgically proven breast cancers who underwent DCE MRI including ultrafast sequence. Based on the TILs level, we classified the patients into the low-TILs (< 10%) group and the high-TILs (≥ 10%) group. Maximum slope (MS) and time to enhancement (TTE) derived from ultrafast DCE sequence were correlated in each TILs group. The percentages of six kinetic patterns (fast, medium, and slow from the early phase, washout, plateau, and persistent from the delayed phase) derived from the conventional DCE sequence were also correlated in each TILs group. RESULTS Of the 76 breast cancers, 57 were in the low-TILs group and 19 comprised the high-TILs group. The median MS in the high-TILs group (32.4%/sec) was significantly higher than that in the low-TILs group (23.68%/s) (p = 0.037). In a receiver-operating characteristic (ROC) analysis, the area under the curve (AUC) for differentiating between the high- and low-TILs group was 0.661. The TTE in the high-TILs group was significantly shorter than that in the low-TILs group (p = 0.012). In the ROC analysis, the AUC was 0.685. There were no significant differences between the percentages of the six kinetic patterns from the conventional DCE sequence and the TILs level (p = 0.075-0.876). CONCLUSION Compared to the low-TILs group, the high-TILs group had higher MS and shorter TTE.
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Affiliation(s)
- Ken Yamaguchi
- Department of Radiology, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
| | - Takahiko Nakazono
- Department of Radiology, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Ryoko Egashira
- Department of Radiology, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Shuichi Fukui
- Department of Radiology, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Tsutomu Imaizumi
- Department of Radiology, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Katsuya Maruyama
- MR Research & Collaboration Department, Siemens Healthcare K.K., Gate City Osaki West Tower, 1-11-1 Osaki, Shinagawa-Ku, Tokyo, 141-8644, Japan
| | - Dominik Nickel
- MR Application Development, Siemens Healthcare GmbH, Allee Am Roethelheimpark 2, 91052, Erlangen, Germany
| | | | - Rin Yamaguchi
- Department of Pathology and Laboratory Medicine, Kurume University Medical Center, 155-1 Kokubu, Kurume, 859-0863, Japan
| | - Hiroyuki Irie
- Department of Radiology, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
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Bansal R, Adeyelu T, Elliott A, Walker P, Bustos MA, Rodriguez E, Accordino MK, Meisel J, Gatti-Mays ME, Hsu E, Lathrop K, Kaklamani V, Oberley M, Sledge G, Sammons SL, Graff SL. Genomic and transcriptomic landscape of HER2-low breast cancer. Breast Cancer Res Treat 2025; 209:323-330. [PMID: 39302579 DOI: 10.1007/s10549-024-07495-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 09/11/2024] [Indexed: 09/22/2024]
Abstract
BACKGROUND Novel agents have expanded the traditional HER2 definitions to include HER2-Low (HER2L) Breast Cancer (BC). We sought to evaluate the distinct molecular characteristics of HER2L BC to understand potential clinical/biologic factors driving resistance and clinical outcomes. METHODS Retrospective analysis was performed on 13,613 BC samples, tested at Caris Life Sciences via NextGen DNA/RNA Sequencing. BC subtypes were defined by IHC/ISH. CODEai database was used to access clinical outcomes from insurance claims data. RESULTS Overall, mutational landscape was similar between HER2L and classical subsets of HR+and HRneg cohorts. TP53 mutations were significantly higher in HRneg/HER2L group vs. HR+/HER2L tumors (p<0.001). A higher mutation rate of PIK3CA was observed in HRneg/HER2L tumors compared to TNBC subtype (p=0.016). PD-L1 positivity was elevated in HRneg/HER2L tumors compared to HR+/HER2L tumors, all p<0.01. Patients with HR+/HER2L tumors treated with CDK4/6 inhibitors had similar OS compared to pts with HR+/HER2-0 (HR=0.89, p=0.012). 27.2% of HR+/HER2L pts had activating PIK3CA mutations. Among HR+PIK3CA mutated tumors, HER2L pts treated with alpelisib showed no difference in OS vs. HER2-0 alpelisib-treated pts (HR=1.23, p=0.517). 13.9% of HER2L TNBC pts were PD-L1+. Interestingly, pts with PD-L1+ HER2L/HRneg (TNBC) treated with immune checkpoint inhibitors (ICI) showed improved OS than HER2-0 TNBC (HR=0.61, p=0.046). CONCLUSION Our findings expand the understanding of the molecular profile of the HER2L subgroup and comparison to the classically defined breast cancer subgroups. Genomic risk assessments after progression on novel therapeutics can be assessed to better define implications for mechanisms of resistance.
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Affiliation(s)
- Rani Bansal
- Duke Cancer Institute, Duke University Hospital, 20 Medicine Circle, Durham, NC, 27710, USA.
| | | | | | | | | | | | - Melissa K Accordino
- Columbia University Herbert Irving Comprehensive Cancer Center, New York, NY, USA
| | - Jane Meisel
- Emory Winship Cancer Center, Atlanta, GA, USA
| | - Margaret E Gatti-Mays
- The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH, USA
| | - Emily Hsu
- Legorreta Cancer Center at Brown University, Providence, RI, USA
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Yohannes M, Massa C, Desalegn Z, Stückrath K, Mueller A, Anberber E, Bekuretsion Y, Assefa M, Santos P, Addissie A, Bauer M, Wickenhauser C, Taylor L, Vetter M, Kantelhardt EJ, Abebe T, Seliger B. Blood immune profiling of Ethiopian patients with breast cancer highlights different forms of immune escape. Oncoimmunology 2024; 13:2436227. [PMID: 39621040 PMCID: PMC11622621 DOI: 10.1080/2162402x.2024.2436227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 11/25/2024] [Accepted: 11/26/2024] [Indexed: 12/08/2024] Open
Abstract
Breast cancer (BC) is a leading cause of death worldwide, particularly also among African woman. In order to better stratify patients for the most effective (immuno-) therapy, an in depth characterization of the immune status of BC patients is required. In this study, a cohort of 65 Ethiopian patients with primary BC underwent immune profiling by multicolor flow cytometry on peripheral blood samples collected prior to surgery and to any other therapy. Comparison with peripheral blood samples from healthy donors highlighted a general activation of the immune system, accompanied by the presence of exhausted CD4+ T cells and senescent CD8+ T cells with an inverted CD4/CD8 ratio in approximately 50% of BC cases. Enhanced frequencies of γδ T cells, myeloid-derived suppressor cells and regulatory T cells were also found. Correlation with clinical parameters demonstrated a progressive reduction in T cell frequencies with increasing histopathological grading of the tumor. Differences in CD8+ T cells and B cells were also noted among luminal and non-luminal BC subtypes. In conclusion, Ethiopian BC patients showed several alterations in the composition and activation status of the blood immune cell repertoire, which were phenotypically associated with immune suppression. The role of these immunological changes in the clinical outcome of patients with BC will have to be determined in follow-up studies and confirmed in additional patients' cohorts.
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Affiliation(s)
- Meron Yohannes
- Department of Microbiology, Immunology & Parasitology, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia
- Department of Medical Laboratory Science, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
- Global and Planetary Health Working Group, Institute of Medical Epidemiology, Biometrics and Informatics, Martin Luther University of Halle-Wittenberg, Halle (Saale), Germany
| | - Chiara Massa
- Institute of Translational Immunology, Brandenburg Medical School “Theodor Fontane”, Brandenburg an der Havel, Germany
| | - Zelalem Desalegn
- Department of Microbiology, Immunology & Parasitology, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia
- Global and Planetary Health Working Group, Institute of Medical Epidemiology, Biometrics and Informatics, Martin Luther University of Halle-Wittenberg, Halle (Saale), Germany
| | - Kathrin Stückrath
- University Clinic and Polyclinic for Gynecology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Anja Mueller
- Institute of Medical Immunology, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Endale Anberber
- Department of Surgery, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia
| | - Yonas Bekuretsion
- Department of Pathology, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia
| | - Mathewos Assefa
- Department of Oncology, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia
| | - Pablo Santos
- Global and Planetary Health Working Group, Institute of Medical Epidemiology, Biometrics and Informatics, Martin Luther University of Halle-Wittenberg, Halle (Saale), Germany
| | - Adamu Addissie
- Global and Planetary Health Working Group, Institute of Medical Epidemiology, Biometrics and Informatics, Martin Luther University of Halle-Wittenberg, Halle (Saale), Germany
- School of Public Health, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Marcus Bauer
- Global and Planetary Health Working Group, Institute of Medical Epidemiology, Biometrics and Informatics, Martin Luther University of Halle-Wittenberg, Halle (Saale), Germany
- Institute of Pathology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Claudia Wickenhauser
- Institute of Pathology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Lesley Taylor
- City of Hope National Medical Center, Duarte, CA, USA
| | - Martina Vetter
- Global and Planetary Health Working Group, Institute of Medical Epidemiology, Biometrics and Informatics, Martin Luther University of Halle-Wittenberg, Halle (Saale), Germany
- University Clinic and Polyclinic for Gynecology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Eva Johanna Kantelhardt
- Global and Planetary Health Working Group, Institute of Medical Epidemiology, Biometrics and Informatics, Martin Luther University of Halle-Wittenberg, Halle (Saale), Germany
- University Clinic and Polyclinic for Gynecology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Tamrat Abebe
- Department of Microbiology, Immunology & Parasitology, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia
- Global and Planetary Health Working Group, Institute of Medical Epidemiology, Biometrics and Informatics, Martin Luther University of Halle-Wittenberg, Halle (Saale), Germany
| | - Barbara Seliger
- Institute of Translational Immunology, Brandenburg Medical School “Theodor Fontane”, Brandenburg an der Havel, Germany
- Institute of Medical Immunology, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
- Department of Cell and Gene Therapy Development, Fraunhofer Institute, Leipzig, Germany
- Faculty of Health Sciences Brandenburg, Brandenburg Medical School “Theodor Fontane”, Institute of Translational Immunology, Brandenburg, Germany
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Toney NJ, Opdenaker LM, Frerichs L, Modarai SR, Ma A, Archinal H, Ajayi GO, Sims-Mourtada J. B cells enhance IL-1 beta driven invasiveness in triple-negative breast cancer. RESEARCH SQUARE 2024:rs.3.rs-5153341. [PMID: 39801513 PMCID: PMC11722549 DOI: 10.21203/rs.3.rs-5153341/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/19/2025]
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype often characterized by high lymphocyte infiltration, including tumor-infiltrating B cells (TIBs). These cells are present even in early stages of TNBC and associated with microinvasion. This study shows that co-culturing TNBC cells with B cells increases Interleukin-1β (IL-1β) expression and secretion. We further show that B cell-induced IL-1β activates NFκB signaling, leading to higher expression of target genes and promoting IL-1β-dependent increases in matrix metalloproteinase (MMP) activity, invasion, and migration. Immunohistochemical analysis of IL-1β and TIBs in triple-negative ductal carcinoma in situ (DCIS, n=90) and invasive TNBC (n=171) revealed that in DCIS, TIBs correlated with IL-1β expression and microinvasion, with IL-1β also linked to recurrence. In invasive TNBC, IL-1β expression correlated with TIB density and stage, with high IL-1β levels associated with poorer survival outcomes. These findings suggest that early B cell presence in TNBC can induce IL-1β secretion, enhancing invasion and mobility through IL-1β-NFκB signaling. This highlights the potential of IL-1 inhibitors as preventive and therapeutic options for hormone receptor-negative DCIS and TNBC.
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Affiliation(s)
| | | | - Lisa Frerichs
- Helen F Graham Cancer Center, and Research Institute
| | | | - Aihui Ma
- Helen F Graham Cancer Center, and Research Institute
| | | | - Grace O Ajayi
- Helen F Graham Cancer Center, and Research Institute
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30
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Bae SJ, Kim JH, Kim MJ, Kook Y, Baek SH, Kim JH, Moon S, Lee SE, Jeong J, Cha YJ, Ahn SG. Stromal tumor-infiltrating lymphocytes and pathologic response to neoadjuvant chemotherapy with the addition of platinum and pembrolizumab in TNBC: a single-center real-world study. Breast Cancer Res 2024; 26:182. [PMID: 39695754 DOI: 10.1186/s13058-024-01944-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 12/04/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Immunochemotherapy with pembrolizumab has been integrated into clinical practice as part of the standard-of-care for non-metastatic triple-negative breast cancer (TNBC) with high risk. We conducted a real-world study in TNBC patients treated with neoadjuvant chemotherapy to compare pathologic complete response (pCR) rates relative to stromal tumor-infiltrating lymphocytes (sTIL) across different regimens: non-carboplatin, carboplatin-, and pembrolizumab-chemotherapy. PATIENTS AND METHODS We analyzed a cohort of 450 patients with TNBC who underwent surgery following neoadjuvant chemotherapy between March 2007 and February 2024. Treatment groups included 247 non-carboplatin, 120 carboplatin, and 83 pembrolizumab-chemotherapy recipients. sTIL was evaluated in biopsied samples. Lymphocyte-predominant breast cancer (LPBC) was defined as tumors with high sTIL (≥ 50%). RESULTS The pCR rates were 32% in the non-carboplatin-, 57% in the carboplatin-, and 64% in the pembrolizumab-chemotherapy group. Ninety-two patients (20.4%) had LPBC. In LPBC, the pCR rates did not increase with the addition of carboplatin (50.0% in the non-carboplatin and 41.7% in carboplatin) but reached 83.3% with the addition of pembrolizumab and carboplatin. Among the non-LPBC, the pCR rate increased from 26.7 to 61.1% with the addition of carboplatin, but there was no difference in the pCR rate between the carboplatin and pembrolizumab groups (61.1% and 61.2%, respectively). CONCLUSIONS In LPBC patients, the addition of carboplatin did not result in an elevated pCR rate; however, the addition of pembrolizumab tended to raise the pCR rate. In non-LPBC, the addition of carboplatin significantly increased the pCR rate, while the addition of pembrolizumab did not have the same effect.
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Affiliation(s)
- Soong June Bae
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute for Breast Cancer Precision Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jee Hung Kim
- Institute for Breast Cancer Precision Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Division of Medical Oncology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Min Ji Kim
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute for Breast Cancer Precision Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Yoonwon Kook
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute for Breast Cancer Precision Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Ho Baek
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute for Breast Cancer Precision Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jung Hyun Kim
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute for Breast Cancer Precision Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sohyun Moon
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute for Breast Cancer Precision Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Eun Lee
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute for Breast Cancer Precision Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Joon Jeong
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute for Breast Cancer Precision Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Yoon Jin Cha
- Institute for Breast Cancer Precision Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
- Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
| | - Sung Gwe Ahn
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
- Institute for Breast Cancer Precision Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
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Cardoso F, Hirshfield KM, Kraynyak KA, Tryfonidis K, Bardia A. Immunotherapy for hormone receptor‒positive HER2-negative breast cancer. NPJ Breast Cancer 2024; 10:104. [PMID: 39643613 PMCID: PMC11624285 DOI: 10.1038/s41523-024-00704-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 10/14/2024] [Indexed: 12/09/2024] Open
Abstract
Additional therapies are needed to improve outcomes in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer. Research on the potential role of immunotherapy, particularly programmed cell death protein 1/programmed cell death ligand 1 inhibitors, is rapidly expanding in both the early and metastatic settings with some preliminary evidence suggesting benefit when used as part of combination therapy. Several ongoing phase 3 studies should help define their future role in treating these patients.
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Affiliation(s)
- Fatima Cardoso
- Breast Unit, Champalimaud Clinical Center/Champalimaud Foundation, Lisbon, Portugal.
| | | | | | | | - Aditya Bardia
- Department of Medicine, Division of Hematology/Oncology, University of California Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
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32
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Culha Y, Ozdemir C, Davarci SE, Ünlü B, Olgun A K M, Demir H, Baykara M. Clinical and prognostic effects of microvascular density and FOXP3 positive T cells in breast cancer. Sci Rep 2024; 14:30341. [PMID: 39639042 PMCID: PMC11621116 DOI: 10.1038/s41598-024-82106-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 12/02/2024] [Indexed: 12/07/2024] Open
Abstract
There are conflicting data regarding the prognostic effect of microvascular density (MVD) in breast cancer and its molecular subtypes. It is thought that high levels of FOXP3 + T cells in breast cancer are associated with poor prognosis. However, data regarding FOXP3 show significant variability in the literature. In our study, we aim to measure MVD and FOXP3 + T cells in breast cancer cases and investigate their relationship with each other and their effects on breast cancer patients' clinical and prognostic features. In our study, the results of 207 female breast cancer patients whose excisional tumoral tissue was obtained are presented. The study evaluated the findings under a light microscope using antibodies against CD34 for measuring MVD and FOXP3 for measuring FOXP3-positive T cells. CD34 ≥ 17 was categorized as high MVD, and CD34 < 17 was classified as low MVD. FOXP3 + cell count ≥ 20/mm2 was categorized as high FOXP3 positivity and < 20/mm2 as low FOXP3 positivity. The SPSS program (version 22) was used to evaluate the results statistically, and p < 0.05 was considered significant. The median age was 54.0 (27-86) years, and the median follow-up period was 60.0 (IQR: 42.6-86.5) months. In the high MVD group, a higher progesterone receptor (PR) positivity rate was detected (p = 0.035). High FOXP3 positivity was significantly associated with high nuclear grade (p = 0.003). High FOXP3 positivity was significantly associated with PR negativity and high Ki67 values (p = 0.009, p = 0.012, respectively). No statistically significant correlation was found between MVD elevation and FOXP3 positivity (r = 0.063, p = 0.36). A weakly significant positive correlation was detected between high Ki67 and FOXP3 positivity (r = 0.0146, p = 0.04). A weak inverse correlation was detected between high FOXP3 positivity and PR percentage values (r=-0.182, p = 0.01). While there was no significant difference in disease-free survival in cases with high MVD and high FOXP3 + T cells compared to groups with low levels, the results were not mature enough because the median values in overall survival could not be reached. A significant correlation was found between high FOXP3 positivity and some aggressive tumor features; no effect on survival was detected. In contrast to literature data on luminal A breast cancer, high MVD in the luminal B (HER2-) subgroup was associated with a lower risk of recurrence. Our study is the first in the literature to evaluate the relationship between MVD measured using CD34 and FOXP3 positive T cells in breast cancer. Our study found no correlation between MVD and FOXP3 positivity, while literature data show significant correlations in some other cancers.
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Affiliation(s)
- Yaşar Culha
- Department of Medical Oncology, Afyonkarahisar Health Sciences University School of Medicine, Afyonkarahisar, Turkey.
| | - Cigdem Ozdemir
- Department of Pathology, Afyonkarahisar Health Sciences University School of Medicine, Afyonkarahisar, Turkey
| | - Sena Ece Davarci
- Department of Medical Oncology, Afyonkarahisar Health Sciences University School of Medicine, Afyonkarahisar, Turkey
| | - Beyza Ünlü
- Department of Medical Oncology, Afyonkarahisar Health Sciences University School of Medicine, Afyonkarahisar, Turkey
| | - Mehmet Olgun A K
- Department of Pathology, Afyonkarahisar Health Sciences University School of Medicine, Afyonkarahisar, Turkey
| | - Hacer Demir
- Department of Medical Oncology, Afyonkarahisar Health Sciences University School of Medicine, Afyonkarahisar, Turkey
| | - Meltem Baykara
- Department of Medical Oncology, Afyonkarahisar Health Sciences University School of Medicine, Afyonkarahisar, Turkey
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Massa D, Vernieri C, Nicolè L, Criscitiello C, Boissière-Michot F, Guiu S, Bobrie A, Griguolo G, Miglietta F, Vingiani A, Lobefaro R, Taurelli Salimbeni B, Pinato C, Schiavi F, Brich S, Pescia C, Fusco N, Pruneri G, Fassan M, Curigliano G, Guarneri V, Jacot W, Dieci MV. Immune and gene-expression profiling in estrogen receptor low and negative early breast cancer. J Natl Cancer Inst 2024; 116:1914-1927. [PMID: 39083015 PMCID: PMC11630536 DOI: 10.1093/jnci/djae178] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 06/25/2024] [Accepted: 07/23/2024] [Indexed: 12/12/2024] Open
Abstract
BACKGROUND The cutoff of <1% positive cells to define estrogen receptor (ER) negativity by immunohistochemistry (IHC) in breast cancer (BC) is debated. We explored the tumor immune microenvironment and gene-expression profile of patients with early-stage HER2-negative ER-low (ER 1%-9%) BC, comparing them to ER-negative (ER <1%) and ER-intermediate (ER 10%-50%) tumors. METHODS Among 921 patients with early-stage I-III, ER ≤50%, HER2-negative BCs, tumors were classified as ER-negative (n = 712), ER-low (n = 128), or ER-intermediate (n = 81). Tumor-infiltrating lymphocytes (TILs) were evaluated. CD8+, FOXP3+ cells, and PD-L1 status were assessed by IHC and quantified by digital pathology. We analyzed 776 BC-related genes in 116 samples. All tests were 2-sided at a <.05 significance level. RESULTS ER-low and ER-negative tumors exhibited similar median TILs, statistically significantly higher than ER-intermediate tumors. CD8/FOXP3 ratio and PD-L1 positivity rates were comparable between ER-low and ER-negative groups. These groups showed similar enrichment in basal-like intrinsic subtypes and comparable expression of immune-related genes. ER-low and ER-intermediate tumors showed significant transcriptomic differences. High TILs (≥30%) were associated with improved relapse-free survival (RFS) in ER-low (5-year RFS 78.6% vs 66.2%, log-rank P = .033, hazard ratio [HR] 0.37 [95% CI = 0.15 to 0.96]) and ER-negative patients (5-year RFS 85.2% vs 69.8%, log-rank P < .001, HR 0.41 [95% CI = 0.27 to 0.60]). CONCLUSIONS ER-low and ER-negative tumors are similar biological and molecular entities, supporting their comparable clinical outcomes and treatment responses, including to immunotherapy. Our findings contribute to the growing evidence calling for a reevaluation of ER-positive BC classification and management, aligning ER-low and ER-negative tumors more closely.
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Affiliation(s)
- Davide Massa
- Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
- Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padova, Padova, Italy
| | - Claudio Vernieri
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- IFOM ETS, The AIRC Institute of Molecular Oncology
| | | | - Carmen Criscitiello
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Division of Early Drug Development for Innovative Therapy, European Institute of Oncology IRCCS, Milan, Italy
| | | | - Séverine Guiu
- Department of Medical Oncology, Institut Régional Du Cancer de Montpellier (ICM), Montpellier, France
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Montpellier University, Montpellier, France
| | - Angélique Bobrie
- Department of Medical Oncology, Institut Régional Du Cancer de Montpellier (ICM), Montpellier, France
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Montpellier University, Montpellier, France
| | - Gaia Griguolo
- Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
- Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padova, Padova, Italy
| | - Federica Miglietta
- Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
- Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padova, Padova, Italy
| | - Andrea Vingiani
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Riccardo Lobefaro
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Beatrice Taurelli Salimbeni
- Division of Early Drug Development for Innovative Therapy, European Institute of Oncology IRCCS, Milan, Italy
| | - Claudia Pinato
- UOSD Hereditary Tumors, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
| | - Francesca Schiavi
- UOSD Hereditary Tumors, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
| | - Silvia Brich
- Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Carlo Pescia
- Division of Pathology, European Institute of Oncology IRCCS, Milan, Italy
| | - Nicola Fusco
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Division of Pathology, European Institute of Oncology IRCCS, Milan, Italy
| | - Giancarlo Pruneri
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), University of Padua, Padova, Italy
- Veneto Institute of Oncology IOV—IRCCS, Padova, Italy
| | - Giuseppe Curigliano
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Division of Early Drug Development for Innovative Therapy, European Institute of Oncology IRCCS, Milan, Italy
| | - Valentina Guarneri
- Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
- Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padova, Padova, Italy
| | - William Jacot
- Translational Research Unit, Institut du Cancer de Montpellier, Montpellier, France
- Department of Medical Oncology, Institut Régional Du Cancer de Montpellier (ICM), Montpellier, France
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Montpellier University, Montpellier, France
| | - Maria Vittoria Dieci
- Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
- Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padova, Padova, Italy
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Verocq C, Noël JC, Charry M, Zindy E, Rorive S, Salmon I, Decaestecker C, Catteau X. Inverse correlation between the amounts of lymphocytic infiltrate and stroma in breast carcinoma. Heliyon 2024; 10:e40295. [PMID: 39641033 PMCID: PMC11617241 DOI: 10.1016/j.heliyon.2024.e40295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 11/07/2024] [Accepted: 11/07/2024] [Indexed: 12/07/2024] Open
Abstract
Background Previous breast carcinoma studies focused on the evaluation of tumour-infiltrating lymphocytes (TILs) or of tumoural stroma via the tumour stroma ratio (TSR). Few studies assessed peritumoural lymphocytes and almost no studies investigated a possible relationship between lymphocytes and stroma. This prompted us to evaluate the amount of tumour cells, intra- and peritumoural lymphocytes, and stroma in breast cancer to support the hypothesis that the stroma may block the infiltration of lymphocytes inside the tumour. Methods We collected a retrospective series of 158 breast cancers (<25 mm). In addition to standard TILs and TSR evaluations, we assessed the percentages of tumour cells, stromal myofibroblasts, intra- and peritumoural lymphocytes on full-section tumours with haematoxylin and eosin and immunohistochemical staining. Results We showed significant negative correlations between the amounts of stroma and both intra- and peritumoural lymphocyte percentages. Considering the estrogen receptor positive invasive breast cancer of no special type cases, we showed that TSR had a positive prognostic value with an optimal threshold of 10 %. Conclusions This study is one of the first to show inverse correlations between tumoural stroma amount and intra- and peritumoural lymphocyte percentages, which supports the hypothesis that tumoural stroma can prevent the recruitment of lymphocytes around and within the tumour.
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Affiliation(s)
- Camille Verocq
- Department of Pathology, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium
- CurePath (Centre Universitaire inter Régional d’Expertise en anatomie Pathologique Hospitalière, CHU Tivoli - CHIREC), Rue de Borfilet, 12A, 6040, Jumet, Belgium
| | - Jean-Christophe Noël
- Department of Pathology, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium
| | - Manon Charry
- CurePath (Centre Universitaire inter Régional d’Expertise en anatomie Pathologique Hospitalière, CHU Tivoli - CHIREC), Rue de Borfilet, 12A, 6040, Jumet, Belgium
| | - Egor Zindy
- DIAPath - Center for Microscopy and Molecular Imaging, ULB, Rue Adrienne Bolland 8, 6041, Gosselies, Belgium
| | - Sandrine Rorive
- Department of Pathology, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium
- CurePath (Centre Universitaire inter Régional d’Expertise en anatomie Pathologique Hospitalière, CHU Tivoli - CHIREC), Rue de Borfilet, 12A, 6040, Jumet, Belgium
| | - Isabelle Salmon
- Department of Pathology, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium
- CurePath (Centre Universitaire inter Régional d’Expertise en anatomie Pathologique Hospitalière, CHU Tivoli - CHIREC), Rue de Borfilet, 12A, 6040, Jumet, Belgium
- DIAPath - Center for Microscopy and Molecular Imaging, ULB, Rue Adrienne Bolland 8, 6041, Gosselies, Belgium
| | - Christine Decaestecker
- DIAPath - Center for Microscopy and Molecular Imaging, ULB, Rue Adrienne Bolland 8, 6041, Gosselies, Belgium
- Laboratory of Image Synthesis and Analysis, Ecole Polytechnique de Bruxelles, ULB, 50, Avenue F. Roosevelt, 1050, Brussels, Belgium
| | - Xavier Catteau
- Department of Pathology, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium
- CurePath (Centre Universitaire inter Régional d’Expertise en anatomie Pathologique Hospitalière, CHU Tivoli - CHIREC), Rue de Borfilet, 12A, 6040, Jumet, Belgium
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Wang X, Venet D, Lifrange F, Larsimont D, Rediti M, Stenbeck L, Dupont F, Rouas G, Garcia AJ, Craciun L, Buisseret L, Ignatiadis M, Carausu M, Bhalla N, Masarapu Y, Villacampa EG, Franzén L, Saarenpää S, Kvastad L, Thrane K, Lundeberg J, Rothé F, Sotiriou C. Spatial transcriptomics reveals substantial heterogeneity in triple-negative breast cancer with potential clinical implications. Nat Commun 2024; 15:10232. [PMID: 39592577 PMCID: PMC11599601 DOI: 10.1038/s41467-024-54145-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 11/02/2024] [Indexed: 11/28/2024] Open
Abstract
While triple-negative breast cancer (TNBC) is known to be heterogeneous at the genomic and transcriptomic levels, spatial information on tumor organization and cell composition is still lacking. Here, we investigate TNBC tumor architecture including its microenvironment using spatial transcriptomics on a series of 92 patients. We perform an in-depth characterization of tumor and stroma organization and composition using an integrative approach combining histomorphological and spatial transcriptomics. Furthermore, a detailed molecular characterization of tertiary lymphoid structures leads to identify a gene signature strongly associated to disease outcome and response to immunotherapy in several tumor types beyond TNBC. A stepwise clustering analysis identifies nine TNBC spatial archetypes, further validated in external datasets. Several spatial archetypes are associated with disease outcome and characterized by potentially actionable features. In this work, we provide a comprehensive insight into the complexity of TNBC ecosystem with potential clinical relevance, opening avenues for treatment tailoring including immunotherapy.
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Affiliation(s)
- Xiaoxiao Wang
- Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Université Libre de Bruxelles, Hôpital Universitaire de Bruxelles, Brussels, Belgium
- Medical Oncology Department, Institut Jules Bordet, Université Libre de Bruxelles, Hôpital Universitaire de Bruxelles, Brussels, Belgium
| | - David Venet
- Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Université Libre de Bruxelles, Hôpital Universitaire de Bruxelles, Brussels, Belgium
| | - Frédéric Lifrange
- Department of Pathology, University Hospital Center of Liège, Liège, Belgium
| | - Denis Larsimont
- Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Hôpital Universitaire de Bruxelles, Brussels, Belgium
| | - Mattia Rediti
- Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Université Libre de Bruxelles, Hôpital Universitaire de Bruxelles, Brussels, Belgium
| | - Linnea Stenbeck
- Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Floriane Dupont
- Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Université Libre de Bruxelles, Hôpital Universitaire de Bruxelles, Brussels, Belgium
| | - Ghizlane Rouas
- Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Université Libre de Bruxelles, Hôpital Universitaire de Bruxelles, Brussels, Belgium
| | - Andrea Joaquin Garcia
- Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Université Libre de Bruxelles, Hôpital Universitaire de Bruxelles, Brussels, Belgium
| | - Ligia Craciun
- Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Hôpital Universitaire de Bruxelles, Brussels, Belgium
| | - Laurence Buisseret
- Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Université Libre de Bruxelles, Hôpital Universitaire de Bruxelles, Brussels, Belgium
- Medical Oncology Department, Institut Jules Bordet, Université Libre de Bruxelles, Hôpital Universitaire de Bruxelles, Brussels, Belgium
| | - Michail Ignatiadis
- Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Université Libre de Bruxelles, Hôpital Universitaire de Bruxelles, Brussels, Belgium
- Medical Oncology Department, Institut Jules Bordet, Université Libre de Bruxelles, Hôpital Universitaire de Bruxelles, Brussels, Belgium
| | - Marcela Carausu
- Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Université Libre de Bruxelles, Hôpital Universitaire de Bruxelles, Brussels, Belgium
| | - Nayanika Bhalla
- Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Yuvarani Masarapu
- Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden
| | | | - Lovisa Franzén
- Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Sami Saarenpää
- Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Linda Kvastad
- Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Kim Thrane
- Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Joakim Lundeberg
- Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Françoise Rothé
- Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Université Libre de Bruxelles, Hôpital Universitaire de Bruxelles, Brussels, Belgium
| | - Christos Sotiriou
- Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Université Libre de Bruxelles, Hôpital Universitaire de Bruxelles, Brussels, Belgium.
- Medical Oncology Department, Institut Jules Bordet, Université Libre de Bruxelles, Hôpital Universitaire de Bruxelles, Brussels, Belgium.
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Rabani S, Gunes EG, Gunes M, Pellegrino B, Lampert B, David K, Pillai R, Li A, Becker-Herman S, Rosen ST, Shachar I. CD84 as a therapeutic target for breaking immune tolerance in triple-negative breast cancer. Cell Rep 2024; 43:114920. [PMID: 39466774 DOI: 10.1016/j.celrep.2024.114920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 07/11/2024] [Accepted: 10/14/2024] [Indexed: 10/30/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. The tumor microenvironment (TME) plays a major regulatory role in TNBC progression and is highly infiltrated by suppressive immune cells that reduce anti-tumor immune activity. Although regulatory B cells (Bregs) are a key TME component, knowledge of their function in TNBC is limited. CD84 is a homophilic adhesion molecule that promotes the survival of blood tumors. In the current study, we followed the role of CD84 in the regulation of the TME in TNBC. We demonstrate that CD84 induces a cascade in Bregs that involves the β-catenin and Tcf4 pathway, which induces the transcription of interleukin-10 by binding to its promoter and the promoter of its regulator, AhR. This leads to the expansion of Bregs, which in turn control the activity of other immune cells and immune suppression. Accordingly, we suggest CD84 as a therapeutic target for breaking immune tolerance in TNBC.
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Affiliation(s)
- Stav Rabani
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Emine Gulsen Gunes
- Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope, Duarte, CA, USA
| | - Martin Gunes
- Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope, Duarte, CA, USA
| | - Bianca Pellegrino
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Bar Lampert
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Keren David
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Raju Pillai
- Pathology Core, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Aimin Li
- Pathology Core, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | | | - Steven T Rosen
- Department of Hematology and Stem Cell Transplantation, City of Hope and Beckman Research Institute, Duarte, CA, USA
| | - Idit Shachar
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
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Shimada K, Michaud DE, Cui YX, Zheng K, Goldberg J, Ju Z, Schnitt SJ, Pastorello R, Kania LD, Hoffer J, Muhlich JL, Hyun N, Krueger R, Gottlieb A, Nelson A, Wanderley CW, Antonellis G, McAllister SS, Tolaney SM, Waks AG, Jeselsohn R, Sorger PK, Agudo J, Mittendorf EA, Guerriero JL. An estrogen receptor signaling transcriptional program linked to immune evasion in human hormone receptor-positive breast cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.23.619172. [PMID: 39651157 PMCID: PMC11623498 DOI: 10.1101/2024.11.23.619172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2024]
Abstract
T cells are generally sparse in hormone receptor-positive (HR+) breast cancer, potentially due to limited antigen presentation, but the driving mechanisms of low T cell abundance remains unclear. Therefore, we defined and investigated programs ('gene modules'), related to estrogen receptor signaling (ERS) and immune signaling using bulk and single-cell transcriptome and multiplexed immunofluorescence of breast cancer tissues from multiple clinical sources and human cell lines. The ERS gene module, dominantly expressed in cancer cells, was negatively associated with immune-related gene modules TNFα/NF-κB signaling and type-I interferon (IFN-I) response, which were expressed in distinct stromal and immune cell types, but also, in part, expressed and preserved as a cancer cell-intrinsic mechanisms. Spatial analysis revealed that ERS strongly correlated with reduced T cell infiltration, potentially due to its association with suppression of TNFα/NF-κB-induced angiogenesis and IFN-I-induced HLA expression in macrophages. Preoperative endocrine therapy in ER+/HER2-breast cancer patients produced better responses in ERS-high patients, with TNFα/NF-κB expression associated with reduced ERS. Targeting these pathways may enhance T cell infiltration in HR+ breast cancer patients. Statement of Significance This study elucidates the immunosuppressive role of ER signaling in breast cancer, highlighting a complex interplay between cancer, stromal, and immune cells and reveals potential approaches to enhance immunogenicity in HR+ breast cancer. These findings offer crucial insights into immune evasion in breast cancer and identify strategies to enhance T cell abundance.
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Yoneyama M, Zormpas-Petridis K, Robinson R, Sobhani F, Provenzano E, Steel H, Lightowlers S, Towns C, Castillo SP, Anbalagan S, Lund T, Wennerberg E, Melcher A, Coles CE, Roxanis I, Yuan Y, Somaiah N. Longitudinal Assessment of Tumor-Infiltrating Lymphocytes in Primary Breast Cancer Following Neoadjuvant Radiation Therapy. Int J Radiat Oncol Biol Phys 2024; 120:862-874. [PMID: 38677525 DOI: 10.1016/j.ijrobp.2024.04.065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 04/16/2024] [Accepted: 04/21/2024] [Indexed: 04/29/2024]
Abstract
PURPOSE Tumor-infiltrating lymphocytes (TILs) have prognostic significance in several cancers, including breast cancer. Despite interest in combining radiation therapy with immunotherapy, little is known about the effect of radiation therapy itself on the tumor-immune microenvironment, including TILs. Here, we interrogated longitudinal dynamics of TILs and systemic lymphocytes in patient samples taken before, during, and after neoadjuvant radiation therapy (NART) from PRADA and Neo-RT breast clinical trials. METHODS AND MATERIALS We manually scored stromal TILs (sTILs) from longitudinal tumor samples using standardized guidelines as well as deep learning-based scores at cell-level (cTIL) and cell- and tissue-level combination analyses (SuperTIL). In parallel, we interrogated absolute lymphocyte counts from routine blood tests at corresponding time points during treatment. Exploratory analyses studied the relationship between TILs and pathologic complete response (pCR) and long-term outcomes. RESULTS Patients receiving NART experienced a significant and uniform decrease in sTILs that did not recover at the time of surgery (P < .0001). This lymphodepletive effect was also mirrored in peripheral blood. Our SuperTIL deep learning score showed good concordance with manual sTILs and importantly performed comparably to manual scores in predicting pCR from diagnostic biopsies. The analysis suggested an association between baseline sTILs and pCR, as well as sTILs at surgery and relapse, in patients receiving NART. CONCLUSIONS This study provides novel insights into TIL dynamics in the context of NART in breast cancer and demonstrates the potential for artificial intelligence to assist routine pathology. We have identified trends that warrant further interrogation and have a bearing on future radioimmunotherapy trials.
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Affiliation(s)
- Miki Yoneyama
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, United Kingdom
| | - Konstantinos Zormpas-Petridis
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, United Kingdom; Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Ruth Robinson
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, United Kingdom; The Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Faranak Sobhani
- Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom
| | - Elena Provenzano
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | - Harriet Steel
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, United Kingdom
| | - Sara Lightowlers
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; Department of Oncology, University of Cambridge, Cambridge, United Kingdom
| | - Catherine Towns
- Department of Oncology, University of Cambridge, Cambridge, United Kingdom
| | - Simon P Castillo
- Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom
| | - Selvakumar Anbalagan
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, United Kingdom
| | - Tom Lund
- Integrated Pathology Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Erik Wennerberg
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, United Kingdom
| | - Alan Melcher
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, United Kingdom
| | - Charlotte E Coles
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; Department of Oncology, University of Cambridge, Cambridge, United Kingdom
| | - Ioannis Roxanis
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Yinyin Yuan
- Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom.
| | - Navita Somaiah
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, United Kingdom; The Royal Marsden NHS Foundation Trust, London, United Kingdom.
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Yin L, Qi Y, Jiang Y. Pharmacological Mechanism of Mume Fructus in the Treatment of Triple-Negative Breast Cancer Based on Network Pharmacology. Appl Biochem Biotechnol 2024; 196:7974-7993. [PMID: 38668843 DOI: 10.1007/s12010-024-04948-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/16/2024] [Indexed: 05/21/2024]
Abstract
Our study aims to find the relevant mechanism of Mume Fructus in the treatment of triple-negative breast cancer (TNBC) by network pharmacology analysis and experimental validation. The effective compounds of Mume Fructus and TNBC-related target genes were imported into Cytoscape to construct a Mume Fructus-effective compounds-disease target network. The common targets of Mume Fructus and TNBC were determined by drawing Venn diagrams. Then, the intersection targets were transferred to the STRING database to construct a protein-protein interaction (PPI) network. To investigate the mechanism of Mume Fructus in treatment of TNBC, breast cancer cell (MDA-MB-231) was treated with Mume Fructus and/or transfected with small interference RNA-PKM2(siPKM2). CCK-8 assay, cell clonal formation assay, transwell, flow cytometry, qRT-PCR, and western blotting were performed. Eight effective compounds and 145 target genes were obtained, and the Mume Fructus- effective compounds-disease target network was constructed. Then through the analysis of the PPI network, we obtained 10 hub genes including JUN, MAPK1, RELA, AKT1, FOS, ESR1, IL6, MAPK8, RXRA, and MYC. KEGG enrichment analysis showed that JUN, MAPK1, RELA, FOS, ESR1, IL6, MAPK8, and RXRA were enriched in the Th17 cell differentiation signaling pathway. Loss of PKM2 and Mume Fructus both inhibited the malignant phenotype of MDA-MB-231 cells. And siPKM2 further aggravated the Mume Fructus inhibition of malignancy of breast cancer cells. Network pharmacology analysis suggests that Mume Fructus has multiple therapeutic targets for TNBC and may play a therapeutic role by modulating the immune microenvironment of breast cancer.
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Affiliation(s)
- Lei Yin
- Department of Breast Surgery, The Second Affiliated Hospital of Shandong First Medical University, Taian, China
| | - Yan Qi
- Operating Theater of the Second Affiliated Hospital of Shandong First Medical University, Taian, China
| | - Yuting Jiang
- Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Shandong First Medical University, Taian, China.
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40
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Li L, Li Y. Role of Ultrasonographic and Clinicopathological Characteristics in Assessing Stromal Tumor-Infiltrating Lymphocyte Density in Triple-Negative Breast Cancer. Balkan Med J 2024; 41:469-475. [PMID: 39324418 PMCID: PMC11589214 DOI: 10.4274/balkanmedj.galenos.2024.2024-7-26] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 08/29/2024] [Indexed: 09/27/2024] Open
Abstract
Background A high density of stromal tumor-infiltrating lymphocytes (sTILs) is positively correlated with the pathological complete response rate and favorable survival in patients with triple-negative breast cancer (TNBC). Heterogeneity in stromal lymphocyte distribution and limited tumor sampling may affect the accuracy of sTIL quantification in biopsy samples from patients receiving neoadjuvant therapy. Thus, identifying additional biomarkers to complement sTIL evaluation is essential. Aims To identify biomarkers that could be used to complement sTILs evaluation. Study Design Retrospective cohort study. Methods A total of 162 patients with invasive TNBC were enrolled in the study. The following data were gathered: sTIL density, Ki67, nuclear grades of cancer cells, lymphovascular invasion status, the American Joint Committee on Cancer stage, axillary lymph node metastasis status, and ultrasonographic parameters of the tumor (size, shape, orientation, margin, internal echo pattern, posterior feature, and vascularity). The relationship between sTIL density and ultrasonographic or clinicopathological characteristics was investigated using both continuous and categorical analyses. Results Posterior features of the primary tumors was associated with sTIL density (p = 0.038). Additionally, the Ki67 levels and nuclear grades were also associated with sTIL density (p < 0.001 and p = 0.024, respectively). When stratified according to a 20% cut-off of sTIL density, the posterior features of primary tumors, Ki67 levels, and nuclear grades significantly differed between the high and low sTIL density tumors. Tumors with high Ki67 levels were more likely to exhibit high sTIL density than low sTIL density [odds ratio (OR): 2.75, p = 0.021]. Furthermore, nuclear grade III tumors demonstrated significantly higher sTIL density than nuclear grade I-II tumors (OR: 2.49, p = 0.014). Additionally, tumors with posterior enhancement or no posterior features were more likely to exhibit high sTIL density than tumors with acoustic shadows (OR: 2.91, p = 0.028; OR: 2.74, p = 0.022, respectively). Conclusion Low sTIL density is frequently observed in tumors exhibiting acoustic shadows on ultrasound. However, high sTIL density is more common in tumors with posterior enhancement or no posterior features. Furthermore, high Ki67 levels (> 40%) and high nuclear grades are positively correlated with high sTIL density. This study findings highlight the need for closer surveillance of these biomarkers to complement sTIL evaluation in TNBC.
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Affiliation(s)
- Lian Li
- Department of Ultrasound Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yingjia Li
- Department of Ultrasound Nanfang Hospital, Southern Medical University, Guangzhou, China
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41
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Haque M, Shyanti RK, Mishra MK. Targeted therapy approaches for epithelial-mesenchymal transition in triple negative breast cancer. Front Oncol 2024; 14:1431418. [PMID: 39450256 PMCID: PMC11499239 DOI: 10.3389/fonc.2024.1431418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 09/24/2024] [Indexed: 10/26/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is distinguished by negative expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), making it an aggressive subtype of breast cancer and contributes to 15-20% of the total incidence. TNBC is a diverse disease with various genetic variations and molecular subtypes. The tumor microenvironment involves multiple cells, including immune cells, fibroblast cells, extracellular matrix (ECM), and blood vessels that constantly interact with tumor cells and influence each other. The ECM undergoes significant structural changes, leading to induced cell proliferation, migration, adhesion, invasion, and epithelial-to-mesenchymal transition (EMT). The involvement of EMT in the occurrence and development of tumors through invasion and metastasis in TNBC has been a matter of concern. Therefore, EMT markers could be prognostic predictors and potential therapeutic targets in TNBC. Chemotherapy has been one of the primary options for treating patients with TNBC, but its efficacy against TNBC is still limited. Targeted therapy is a critical emerging option with enhanced efficacy and less adverse effects on patients. Various targeted therapy approaches have been developed based on the specific molecules and the signaling pathways involved in TNBC. These include inhibitors of signaling pathways such as TGF-β, Wnt/β-catenin, Notch, TNF-α/NF-κB and EGFR, as well as immune checkpoint inhibitors, such as pembrolizumab, 2laparib, and talazoparib have been widely explored. This article reviews recent developments in EMT in TNBC invasion and metastasis and potential targeted therapy strategies.
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Affiliation(s)
| | | | - Manoj K. Mishra
- Cancer Research Center, Department of Biological Sciences, Alabama State
University, Montgomery, AL, United States
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42
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Elias AD, Staley AW, Fornier M, Vidal GA, Alami V, Sams S, Spoelstra NS, Goodspeed A, Kabos P, Diamond JR, Shagisultanova E, Gallagher RI, Wulfkuhle JD, Petricoin EF, Zolman KL, McSpadden T, Jordan KR, Slansky JE, Borges VF, Gao D, Richer JK. Clinical and immune responses to neoadjuvant fulvestrant with or without enzalutamide in ER+/Her2- breast cancer. NPJ Breast Cancer 2024; 10:88. [PMID: 39368973 PMCID: PMC11455938 DOI: 10.1038/s41523-024-00697-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 09/22/2024] [Indexed: 10/07/2024] Open
Abstract
Most ER+ breast cancers (BC) express androgen receptors (AR). This randomized phase II trial of 4 months of neoadjuvant fulvestrant (Fulv) alone or with enzalutamide (Combo) assessed whether adding AR blockade to Fulv would limit residual tumor at the time of surgery, as measured by modified preoperative endocrine predictive index (PEPI) score. Eligible patients were women with ER+/HER2- primary BC cT2 or greater. Stratification factors were clinical node and T-stage. Fresh tumor biopsies were required at study entry, after 4 weeks on therapy (W5), and at surgery. Laboratory analyses on tumors included immunochemistry (IHC) for ER/PR/AR/GR and Ki67 protein, evaluation of gene expression, multiplex for myeloid lineage immune cells, reverse-phase protein array, and plasma metabolomic analyses. Of 69 consented patients, 59 were evaluable. Toxicity was as expected with endocrine therapy. Combo achieved PEPI = 0 more frequently (24%: 8/33) than Fulv (8%: 2/26). Ki67 was ≤10% across arms by W5 in 76% of tumors. Activation of mTOR pathway proteins was elevated in tumors with poor Ki67 response. Tumors in both arms showed decreased estrogen-regulated and cell division gene sets, while Combo arm tumors uniquely exhibited enrichment of immune activation gene sets, including interferon gamma, complement, inflammation, antigen processing, and B and T cell activation. Multiplex IHC showed significantly reduced tumor-associated macrophages and CD14+/HLADR-/CD68- MDSCs in Combo tumors at W5. In summary, Combo tumors showed a higher PEPI = 0 response, Ki67 response, and more activated tumor immune microenvironment than Fulv. The odds of response were 4.6-fold higher for patients with ILC versus IDC. (Trial registration: This trial is registered at Clinicaltrials.gov ( https://www.clinicaltrials.gov/study/NCT02955394?id=16-1042&rank=1 ). The trial registration number is NCT02955394. The full trial protocol is available under Study Details at the Clinicaltrials.gov link provided).
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Affiliation(s)
- Anthony D Elias
- Department of Medicine/Medical Oncology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Alyse W Staley
- Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
- University of Colorado Cancer Center, Biostatistics and Bioinformatics Shared Resource, Aurora, Colorado, USA
| | - Monica Fornier
- Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Gregory A Vidal
- West Cancer Center and Research Institute and Department of Medicine, University of Tennessee Health Sciences Center, Tennessee, USA
| | - Vida Alami
- University of Colorado Cancer Center, Biostatistics and Bioinformatics Shared Resource, Aurora, Colorado, USA
| | - Sharon Sams
- Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Nicole S Spoelstra
- Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Andrew Goodspeed
- University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Peter Kabos
- Department of Medicine/Medical Oncology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Jennifer R Diamond
- Department of Medicine/Medical Oncology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Elena Shagisultanova
- Department of Medicine/Medical Oncology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Rosa I Gallagher
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, Virginia, USA
| | - Julia D Wulfkuhle
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, Virginia, USA
| | - Emanuel F Petricoin
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, Virginia, USA
| | - Kathryn L Zolman
- Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Tessa McSpadden
- University of Colorado Cancer Center, Oncology Clinical Research Support Team, Aurora, Colorado, USA
| | - Kimberly R Jordan
- Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Jill E Slansky
- Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Virginia F Borges
- Department of Medicine/Medical Oncology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Dexiang Gao
- Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
- University of Colorado Cancer Center, Biostatistics and Bioinformatics Shared Resource, Aurora, Colorado, USA
| | - Jennifer K Richer
- Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA.
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Cha SM, Park JW, Lee YJ, Lee HJ, Lee H, Lee IW, Gong G, Park SH, Lee HJ, Jeong BK. SPP1+ macrophages in HR+ breast cancer are associated with tumor-infiltrating lymphocytes. NPJ Breast Cancer 2024; 10:83. [PMID: 39349495 PMCID: PMC11442831 DOI: 10.1038/s41523-024-00695-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 09/22/2024] [Indexed: 10/02/2024] Open
Abstract
Breast cancer categorized into hormone receptor-positive (HR+), HER2-positive (HER2+), and triple-negative (TNBC) subtypes, exhibits varied outcomes based on the number of tumor-infiltrating lymphocytes (TILs). To explore the divergent roles of TIL levels across different subtypes, we employed single-cell RNA sequencing on 31 patients with breast cancer. HR+ breast cancer with high TIL levels (TIL-high) revealed increased SPP1+ macrophages, increased SPP1 expression in other monocytes/macrophages (mono/macro) subgroups, and enriched pathways associated with extracellular matrix (ECM) remodeling in mono/macro. Moreover, cell-cell interaction analyses revealed enhanced SPP1, MIF, and FN1 signaling in the interaction between SPP1+ macrophages and T-cells in TIL-high HR+ breast cancer. Spatial transcriptomics data highlighted the close proximity of SPP1+ macrophages, CD8+ T-cells, and CD4+ T-cells in TIL-high HR+ breast cancer. Our findings unveil the novel influence of SPP1+ macrophages on T-cells in TIL-high HR+ breast cancer, potentially explaining the poor prognosis and offering insights for targeted interventions.
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Grants
- A20221175 Asan Institute for Life Sciences, Asan Medical Center
- A20221175 Asan Institute for Life Sciences, Asan Medical Center
- A20221175 Asan Institute for Life Sciences, Asan Medical Center
- A20221175 Asan Institute for Life Sciences, Asan Medical Center
- A20221175 Asan Institute for Life Sciences, Asan Medical Center
- A20221175 Asan Institute for Life Sciences, Asan Medical Center
- A20221175 Asan Institute for Life Sciences, Asan Medical Center
- A20221175 Asan Institute for Life Sciences, Asan Medical Center
- A20221175 Asan Institute for Life Sciences, Asan Medical Center
- A20221175 Asan Institute for Life Sciences, Asan Medical Center
- NRF-2018R1D1A1B07048831 National Research Foundation of Korea (NRF)
- NRF-2018R1D1A1B07048831 National Research Foundation of Korea (NRF)
- NRF-2018R1D1A1B07048831 National Research Foundation of Korea (NRF)
- NRF-2018R1D1A1B07048831 National Research Foundation of Korea (NRF)
- NRF-2018R1D1A1B07048831 National Research Foundation of Korea (NRF)
- NRF-2018R1D1A1B07048831 National Research Foundation of Korea (NRF)
- NRF-2018R1D1A1B07048831 National Research Foundation of Korea (NRF)
- NRF-2018R1D1A1B07048831 National Research Foundation of Korea (NRF)
- NRF-2018R1D1A1B07048831 National Research Foundation of Korea (NRF)
- NRF-2018R1D1A1B07048831 National Research Foundation of Korea (NRF)
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Affiliation(s)
- Su Min Cha
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
- Biomedical Sciences, Asan Medical Institute of Convergence Science and Technology (AMIST), University of Ulsan College of Medicine, Seoul, South Korea
| | | | - Yoon Jae Lee
- University of Ulsan College of Medicine, Seoul, South Korea
| | | | | | | | - Gyungyub Gong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Sung Hee Park
- School of Systems Biomedical Science, Soongsil University, Seoul, Republic of Korea
| | - Hee Jin Lee
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
- Biomedical Sciences, Asan Medical Institute of Convergence Science and Technology (AMIST), University of Ulsan College of Medicine, Seoul, South Korea.
- NeogenTC Corp., Seoul, South Korea.
| | - Byung-Kwan Jeong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
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Vilela T, Valente S, Correia J, Ferreira F. Advances in immunotherapy for breast cancer and feline mammary carcinoma: From molecular basis to novel therapeutic targets. Biochim Biophys Acta Rev Cancer 2024; 1879:189144. [PMID: 38914239 DOI: 10.1016/j.bbcan.2024.189144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 05/29/2024] [Accepted: 06/19/2024] [Indexed: 06/26/2024]
Abstract
The role of inflammation in cancer is a topic that has been investigated for many years. As established, inflammation emerges as a defining characteristic of cancer, presenting itself as a compelling target for therapeutic interventions in the realm of oncology. Controlling the tumor microenvironment (TME) has gained paramount significance, modifying not only the effectiveness of immunotherapy but also modulating the outcomes and prognoses of standard chemotherapy and other anticancer treatments. Immunotherapy has surfaced as a central focus within the domain of tumor treatments, using immune checkpoint inhibitors as cancer therapy. Immune checkpoints and their influence on the tumor microenvironment dynamic are presently under investigation, aiming to ascertain their viability as therapeutic interventions across several cancer types. Cancer presents a significant challenge in humans and cats, where female breast cancer ranks as the most prevalent malignancy and feline mammary carcinoma stands as the third most frequent. This review seeks to summarize the data about the immune checkpoints cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), lymphocyte activation gene-3 (LAG-3), programmed cell death protein-1 (PD-1), V-domain Ig suppressor of T cell activation (VISTA), and T-cell immunoglobulin and mucin domain 3 (TIM-3) respective ongoing investigations as prospective targets for therapy for human breast cancer, while also outlining findings from studies reported on feline mammary carcinoma (FMC), strengthening the rationale for employing FMC as a representative model in the exploration of human breast cancer.
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Affiliation(s)
- Tatiana Vilela
- Faculty of Veterinary Medicine, University of Lisbon, Avenida da Universidade Técnica, 1300-477 Lisbon, Portugal
| | - Sofia Valente
- Faculty of Veterinary Medicine, University of Lisbon, Avenida da Universidade Técnica, 1300-477 Lisbon, Portugal
| | - Jorge Correia
- Faculty of Veterinary Medicine, University of Lisbon, Avenida da Universidade Técnica, 1300-477 Lisbon, Portugal; CIISA-Center of Interdisciplinary Research in Animal Health, 1300-477 Lisbon, Portugal; Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), 1300-477 Lisbon, Portugal
| | - Fernando Ferreira
- Faculty of Veterinary Medicine, University of Lisbon, Avenida da Universidade Técnica, 1300-477 Lisbon, Portugal; CIISA-Center of Interdisciplinary Research in Animal Health, 1300-477 Lisbon, Portugal; Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), 1300-477 Lisbon, Portugal.
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Grasset EM, Deshpande A, Lee JW, Cho Y, Shin SM, Coyne EM, Hernandez A, Yuan X, Zhang Z, Cimino-Mathews A, Ewald AJ, Ho WJ. Mapping the breast tumor microenvironment: proximity analysis reveals spatial relationships between macrophage subtypes and metastasis-initiating cancer cells. Oncogene 2024; 43:2927-2937. [PMID: 39164522 DOI: 10.1038/s41388-024-03127-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 07/30/2024] [Accepted: 08/06/2024] [Indexed: 08/22/2024]
Abstract
Metastasis is responsible for the majority of cancer-related fatalities. We previously identified specific cancer cell populations responsible for metastatic events which are cytokeratin-14 (CK14) and E-cadherin positive in luminal tumors, and E-cadherin and vimentin positive in triple-negative tumors. Since cancer cells evolve within a complex ecosystem comprised of immune cells and stromal cells, we sought to decipher the spatial interactions of these aggressive cancer cell populations within the tumor microenvironment (TME). We used imaging mass cytometry to detect 36 proteins in tumor microarrays containing paired primary and metastatic lesions from luminal or triple-negative breast cancers (TNBC), resulting in a dataset of 1,477,337 annotated cells. Focusing on metastasis-initiating cell populations, we observed close proximity to specific fibroblast and macrophage subtypes, a relationship maintained between primary and metastatic tumors. Notably, high CK14 in luminal cancer cells and high vimentin in TNBC cells correlated with close proximity to specific macrophage subtypes (CD163intCD206intPDL1intHLA-DR+ or PDL1highARG1high). Our in-depth spatial analysis demonstrates that metastasis-initiating cancer cells consistently colocalizes with distinct cell populations within the TME, suggesting a role for these cell-cell interactions in promoting metastasis.
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Affiliation(s)
- Eloïse M Grasset
- Université de Nantes, INSERM, CNRS, CRCI2NA, Nantes, France.
- Équipe Labellisée LIGUE Contre le Cancer CRCI2NA, Nantes, France.
- Department of Cell Biology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
| | - Atul Deshpande
- Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
- Convergence Institute, Johns Hopkins University, Baltimore, MD, USA
- Department of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Jae W Lee
- Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Yeonju Cho
- Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Sarah M Shin
- Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Erin M Coyne
- Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Alexei Hernandez
- Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Xuan Yuan
- Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Zhehao Zhang
- Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Ashley Cimino-Mathews
- Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Andrew J Ewald
- Department of Cell Biology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
- Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
- Convergence Institute, Johns Hopkins University, Baltimore, MD, USA
- Giovanis Institute for Translational Cell Biology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Won Jin Ho
- Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
- Convergence Institute, Johns Hopkins University, Baltimore, MD, USA.
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Stanton S, Schmitz F, Copeland W, DellAringa J, Newhall K, Disis M. Populations of triple negative and hormone receptor positive HER2 negative breast tumors share immune gene profiles. RESEARCH SQUARE 2024:rs.3.rs-4542494. [PMID: 39149486 PMCID: PMC11326399 DOI: 10.21203/rs.3.rs-4542494/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/17/2024]
Abstract
In breast cancer, triple negative (TN) breast cancer has most responses to immune checkpoint inhibitor (ICI) therapy. Lymphocyte infiltrate does not impact prognosis in Hormone receptor positive HER2 negative (HR + HER2-) breast tumors and few HR + HER2- tumors respond to ICI. We contrasted immune-associated gene expression between 119 TN and 475 HR + HER2- breast tumors from The Cancer Genome Atlas (TCGA) and confirmed our findings in 299 TN and 1369 HR + HER2- breast tumors in the METABRIC database. TN and HR+ HER2- tumors grouped into immune-high or -low tumors, both subtypes were represented in the immune-high group. The largest difference between the immune-high TN and HR + HER2- tumors was TN tumors had more abundant Th1 and Th2 CD4+ T cells while HR + HER2- tumors had more abundant fibroblasts (log2FC > 0.3; p < 10×10-10). This suggests an immune-high signature is not dictated by breast cancer subtype, but fibroblast subsets associated with worse outcome were higher in the immune-high HR + HER2- tumors.
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Zhao Z, Ma X, Cai Z. The potential role of CD8+ cytotoxic T lymphocytes and one branch connected with tissue-resident memory in non-luminal breast cancer. PeerJ 2024; 12:e17667. [PMID: 39006029 PMCID: PMC11246025 DOI: 10.7717/peerj.17667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 06/11/2024] [Indexed: 07/16/2024] Open
Abstract
Advances in understanding the pathological mechanisms of breast cancer have resulted in the emergence of novel therapeutic strategies. However, triple-negative breast cancer (TNBC), a molecular subtype of breast cancer with a poor prognosis, lacks classical and general therapeutic targets, hindering the clinical application of several therapies to breast cancer. As insights into the unique immunity and molecular mechanisms of TNBC have become more extensive, immunotherapy has gradually become a valuable complementary approach to classical radiotherapy and chemotherapy. CD8+ cells are significant actors in the tumor immunity cycle; thus, research on TNBC immunotherapy is increasingly focused in this direction. Recently, CD8+ tissue-resident memory (TRM) cells, a subpopulation of CD8+ cells, have been explored in relation to breast cancer and found to seemingly play an undeniably important role in tumor surveillance and lymphocytic infiltration. In this review, we summarize the recent advances in the mechanisms and relative targets of CD8+ T cells, and discuss the features and potential applications of CD8+ TRM cells in non-luminal breast cancer immunotherapy.
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Affiliation(s)
- Ziqi Zhao
- Department of Breast Cancer, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
| | - Xinyu Ma
- Department of Breast Cancer, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
| | - Zhengang Cai
- Department of Breast Cancer, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
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Dvir K, Giordano S, Leone JP. Immunotherapy in Breast Cancer. Int J Mol Sci 2024; 25:7517. [PMID: 39062758 PMCID: PMC11276856 DOI: 10.3390/ijms25147517] [Citation(s) in RCA: 23] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 06/29/2024] [Accepted: 07/04/2024] [Indexed: 07/28/2024] Open
Abstract
Breast cancer is a disease encompassing a spectrum of molecular subtypes and clinical presentations, each with distinct prognostic implications and treatment responses. Breast cancer has traditionally been considered an immunologically "cold" tumor, unresponsive to immunotherapy. However, clinical trials in recent years have found immunotherapy to be an efficacious therapeutic option for select patients. Breast cancer is categorized into different subtypes ranging from the most common positive hormone receptor (HR+), human epidermal growth factor receptor 2 (HER2)-negative type, to less frequent HER2- positive breast cancer and triple-negative breast cancer (TNBC), highlighting the necessity for tailored treatment strategies aimed at maximizing patient outcomes. Despite notable progress in early detection and new therapeutic modalities, breast cancer remains the second leading cause of cancer death in the USA. Moreover, in recent decades, breast cancer incidence rates have been increasing, especially in women younger than the age of 50. This has prompted the exploration of new therapeutic approaches to address this trend, offering new therapeutic prospects for breast cancer patients. Immunotherapy is a class of therapeutic agents that has revolutionized the treatment landscape of many cancers, namely melanoma, lung cancer, and gastroesophageal cancers, amongst others. Though belatedly, immunotherapy has entered the treatment armamentarium of breast cancer, with the approval of pembrolizumab in combination with chemotherapy in triple-negative breast cancer (TNBC) in the neoadjuvant and advanced settings, thereby paving the path for further research and integration of immune checkpoint inhibitors in other subtypes of breast cancer. Trials exploring various combination therapies to harness the power of immunotherapy in symbiosis with various chemotherapeutic agents are ongoing in hopes of improving response rates and prolonging survival for breast cancer patients. Biomarkers and precise patient selection for the utilization of immunotherapy remain cardinal and are currently under investigation, with some biomarkers showing promise, such as Program Death Lignat-1 (PDL-1) Combined Positive Score, Tumor Mutation Burden (TMB), and Tumor Infiltrating Lymphocytes (TILs). This review will present the current landscape of immunotherapy, particularly checkpoint inhibitors, in different types of breast cancer.
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Affiliation(s)
- Kathrin Dvir
- Dana Farber Cancer Institute, Boston, MA 02215, USA; (K.D.)
- St. Elizabeth’s Medical Center, Boston, MA 02111, USA
| | - Sara Giordano
- Dana Farber Cancer Institute, Boston, MA 02215, USA; (K.D.)
- St. Elizabeth’s Medical Center, Boston, MA 02111, USA
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Afzal MZ, Vahdat LT. Evolving Management of Breast Cancer in the Era of Predictive Biomarkers and Precision Medicine. J Pers Med 2024; 14:719. [PMID: 39063972 PMCID: PMC11278458 DOI: 10.3390/jpm14070719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 06/17/2024] [Accepted: 06/30/2024] [Indexed: 07/28/2024] Open
Abstract
Breast cancer is the most common cancer among women in the world as well as in the United States. Molecular and histological differentiation have helped clinicians optimize treatments with various therapeutics, including hormonal therapy, chemotherapy, immunotherapy, and radiation therapy. Recently, immunotherapy has become the standard of care in locally advanced triple-negative breast cancer and an option across molecular subtypes for tumors with a high tumor mutation burden. Despite the advancements in personalized medicine directing the management of localized and advanced breast cancers, the emergence of resistance to these therapies is the leading cause of death among breast cancer patients. Therefore, there is a critical need to identify and validate predictive biomarkers to direct treatment selection, identify potential responders, and detect emerging resistance to standard therapies. Areas of active scientific and clinical research include novel personalized and predictive biomarkers incorporating tumor microenvironment, tumor immune profiling, molecular characterization, and histopathological differentiation to predict response and the potential emergence of resistance.
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Affiliation(s)
- Muhammad Zubair Afzal
- Medical Oncology, Comprehensive Breast Program, Dartmouth Cancer Center, Lebanon, NH 03755, USA
| | - Linda T. Vahdat
- Medical Oncology and Hematology (Interim), Dartmouth Cancer Center, Lebanon, NH 03755, USA;
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Wu H, Wu Z, Li H, Wang Z, Chen Y, Bao J, Chen B, Xu S, Xia E, Ye D, Dai X. Glycosylphosphatidylinositol anchor biosynthesis pathway-based biomarker identification with machine learning for prognosis and T cell exhaustion status prediction in breast cancer. Front Immunol 2024; 15:1392940. [PMID: 39015576 PMCID: PMC11249538 DOI: 10.3389/fimmu.2024.1392940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 06/11/2024] [Indexed: 07/18/2024] Open
Abstract
As the primary component of anti-tumor immunity, T cells are prone to exhaustion and dysfunction in the tumor microenvironment (TME). A thorough understanding of T cell exhaustion (TEX) in the TME is crucial for effectively addressing TEX in clinical settings and promoting the efficacy of immune checkpoint blockade therapies. In eukaryotes, numerous cell surface proteins are tethered to the plasma membrane via Glycosylphosphatidylinositol (GPI) anchors, which play a crucial role in facilitating the proper translocation of membrane proteins. However, the available evidence is insufficient to support any additional functional involvement of GPI anchors. Here, we investigate the signature of GPI-anchor biosynthesis in the TME of breast cancer (BC)patients, particularly its correlation with TEX. GPI-anchor biosynthesis should be considered as a prognostic risk factor for BC. Patients with high GPI-anchor biosynthesis showed more severe TEX. And the levels of GPI-anchor biosynthesis in exhausted CD8 T cells was higher than normal CD8 T cells, which was not observed between malignant epithelial cells and normal mammary epithelial cells. In addition, we also found that GPI -anchor biosynthesis related genes can be used to diagnose TEX status and predict prognosis in BC patients, both the TEX diagnostic model and the prognostic model showed good AUC values. Finally, we confirmed our findings in cells and clinical samples. Knockdown of PIGU gene expression significantly reduced the proliferation rate of MDA-MB-231 and MCF-7 cell lines. Immunofluorescence results from clinical samples showed reduced aggregation of CD8 T cells in tissues with high expression of GPAA1 and PIGU.
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Affiliation(s)
- Haodong Wu
- Department of Breast Surgery, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhixuan Wu
- Department of Breast Surgery, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Hongfeng Li
- Department of Breast Surgery, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ziqiong Wang
- Department of Breast Surgery, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yao Chen
- Department of Breast Surgery, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jingxia Bao
- Department of Breast Surgery, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Buran Chen
- School of Molecular Science, University of Western Australia, Perth, WA, Australia
| | - Shuning Xu
- Department of Computer Information Systems, Georgia State University, Atlanta, GA, United States
| | - Erjie Xia
- Department of Breast Surgery, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Daijiao Ye
- Department of Breast Surgery, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xuanxuan Dai
- Department of Breast Surgery, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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