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Kim DH, Kang M, Park G, Mostafavi M, Lim Y, Ock CY, Koh J, Jeon YK, Jung KC, Ahn SH, Chung EJ, Kwon SK, Keam B. Changes in the tumor microenvironment in recurrent head and neck squamous cell carcinoma and its implication on efficacy of immune checkpoint inhibitors. Discov Oncol 2024; 15:686. [PMID: 39567471 PMCID: PMC11579274 DOI: 10.1007/s12672-024-01504-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 11/01/2024] [Indexed: 11/22/2024] Open
Abstract
Little is known about changes in the abundance of tumor-infiltrating lymphocytes (TILs) and immune phenotype (IP) in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). We aimed to compare the TILs and IP between initial and recurrent HNSCCs using paired analysis. Thirty-seven patients who experienced recurrence after surgical resection and received treatment with immune checkpoint inhibitors (ICIs) between June 2014 and June 2023 were included. Changes in intratumoral TIL (iTILs), stromal TIL (sTILs), and IPs were subjected to paired analysis between the initial and recurrent tumors. We investigated their relationship with the outcomes of ICIs. The density of iTIL and sTIL in the recurrent tumors was significantly lower compared to initial tumors. IP was significantly different; the proportion of desert IP was higher in recurrent tumors (83.8% vs. 35.1%, P < 0.001). Increased sTIL was a favorable indicator for overall response to ICIs and progression-free survival. Our findings suggest TILs decrease during recurrence compared with the initial tumor, resulting in a transition toward desert IP. Therefore, careful evaluation of TIL density in both initial and recurrent tumors is recommended when using ICIs in patients with R/M HNSCC.
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Affiliation(s)
- Dong Hyun Kim
- Department of Internal Medicine, Seoul National University Hospital, 101, Daehak-Ro, Jongro-Gu, Seoul, 03080, Republic of Korea
- Department of Translational Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | | | | | | | | | | | - Jiwon Koh
- Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yoon Kyung Jeon
- Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Kyeong Cheon Jung
- Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Soon-Hyun Ahn
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Republic of Korea
| | - Eun-Jae Chung
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Republic of Korea
| | - Seong-Keun Kwon
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Republic of Korea
| | - Bhumsuk Keam
- Department of Internal Medicine, Seoul National University Hospital, 101, Daehak-Ro, Jongro-Gu, Seoul, 03080, Republic of Korea.
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
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Egelston CA, Guo W, Simons DL, Ye J, Avalos C, Solomon ST, Nwangwu M, Nelson MS, Tan J, Bacon ER, Ihle K, Schmolze D, Tumyan L, Waisman JR, Lee PP. Organ-Specific Immune Setpoints Underlie Divergent Immune Profiles across Metastatic Sites in Breast Cancer. Cancer Immunol Res 2024; 12:1559-1573. [PMID: 39051632 PMCID: PMC11534553 DOI: 10.1158/2326-6066.cir-23-0718] [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: 08/30/2023] [Revised: 03/06/2024] [Accepted: 07/23/2024] [Indexed: 07/27/2024]
Abstract
Immune composition within the tumor microenvironment (TME) plays a central role in the propensity of cancer cells to metastasize and respond to therapy. Previous studies have suggested that the metastatic TME is immune-suppressed. However, limited accessibility to multiple metastatic sites within patients has made assessing the immune TME difficult in the context of multiorgan metastases. We utilized a rapid postmortem tissue collection protocol to assess the immune composition of numerous sites of breast cancer metastasis and paired tumor-free tissues. Metastases had comparable immune cell densities and compositions to paired tumor-free tissues of the same organ type. In contrast, immune cell densities in both metastatic and tumor-free tissues differed significantly between organ types, with lung immune infiltration being consistently greater than that in the liver. These immune profiling results were consistent between flow cytometry and multiplex immunofluorescence-based spatial analysis. Furthermore, we found that granulocytes were the predominant tumor-infiltrating immune cells in lung and liver metastases, and these granulocytes comprised most PD-L1-expressing cells in many tissue sites. We also identified distinct potential mechanisms of immunosuppression in lung and liver metastases, with the lung having increased expression of PD-L1+ antigen-presenting cells and the liver having higher numbers of activated regulatory T cells and HLA-DRlow monocytes. Together, these results demonstrate that the immune contexture of metastases is dictated by organ type and that immunotherapy strategies may benefit from unique tailoring to the tissue-specific features of the immune TME.
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Affiliation(s)
- Colt A. Egelston
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA
| | - Weihua Guo
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA
| | - Diana L. Simons
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA
| | - Jian Ye
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA
| | - Christian Avalos
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA
| | - Shawn T. Solomon
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA
| | - Mary Nwangwu
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA
| | - Michael S. Nelson
- The Light Microscopy and Digital Imaging Core, Beckman Research Institute, City of Hope, Duarte, CA
| | - Jiayi Tan
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA
| | - Eliza R. Bacon
- Department of Medical Oncology, City of Hope, Duarte, CA
| | - Kena Ihle
- Department of Medical Oncology, City of Hope, Duarte, CA
| | | | - Lusine Tumyan
- Department of Diagnostic Radiology, City of Hope, Duarte, CA
| | | | - Peter P. Lee
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA
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Aboelnasr LS, Meehan H, Saso S, Yagüe E, El-Bahrawy M. Serous Ovarian Carcinoma: Detailed Analysis of Clinico-Pathological Characteristics as Prognostic Factors. Cancers (Basel) 2024; 16:3611. [PMID: 39518051 PMCID: PMC11545192 DOI: 10.3390/cancers16213611] [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: 09/29/2024] [Revised: 10/21/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND/OBJECTIVES Serous ovarian carcinoma (SOC) is the most common subtype of epithelial ovarian cancer, with high-grade (HGSOC) and low-grade (LGSOC) subtypes presenting distinct clinical behaviours. This study aimed to evaluate histopathologic features in SOC, correlating these with prognostic outcomes, and explore the potential clinical implications. METHODS We analysed 51 SOC cases for lymphovascular space invasion (LVSI), tumour border configuration (TBC), microvessel density (MVD), tumour budding (TB), the tumour-stroma ratio (TSR), the stromal type, tumour-infiltrating lymphocytes (TILs), and tertiary lymphoid structures (TLSs). A validation cohort of 54 SOC cases from The Cancer Genome Atlas (TCGA) was used for comparison. RESULTS In the discovery set, significant predictors of aggressive behaviour included LVSI, high MVD, high TB, and low TILs. These findings were validated in the validation set where the absence of TLSs, lower peritumoural TILs, immature stromal type, and low TSR were associated with worse survival outcomes. The stromal type was identified as an independent prognostic predictor in SOC across both datasets. Inter-observer variability analysis demonstrated substantial to almost perfect agreement for these features, ensuring the reproducibility of the findings. CONCLUSIONS The histopathological evaluation of immune and stromal features, such as TILs, TLSs, TB, TSR, and stromal type, provides critical prognostic information for SOC. Incorporating these markers into routine pathological assessments could enhance risk stratification and guide treatment, offering practical utility, particularly in low-resource settings when molecular testing is not feasible.
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Affiliation(s)
- Lamia Sabry Aboelnasr
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK; (L.S.A.); (S.S.)
- Department of Pathology, Faculty of Medicine, Menoufia University, Shibin el Kom 6131567, Egypt
| | - Hannah Meehan
- Imperial College NHS Healthcare Trust, London W12 0NN, UK;
| | - Srdjan Saso
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK; (L.S.A.); (S.S.)
- Hammersmith Hospital, Imperial College NHS Trust, London W12 OHS, UK
| | - Ernesto Yagüe
- Division of Cancer, Imperial College London, London W12 0NN, UK;
| | - Mona El-Bahrawy
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK; (L.S.A.); (S.S.)
- Department of Pathology, Faculty of Medicine, University of Alexandria, Bab Sharqi 5424041, Egypt
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Kim DH, Ahn JS, Kang M, Park G, Lim Y, Hwang S, Ock CY, Koh J, Chung EJ, Kwon SK, Jeon YK, Jung KC, Ahn SH, Keam B. Comparison of Tumor Microenvironments between Primary Tumors and Lymph Node Metastases in Head and Neck Squamous Cell Carcinoma and Their Predictive Role in Immune Checkpoint Inhibitor Treatment. Cells 2024; 13:1557. [PMID: 39329741 PMCID: PMC11429639 DOI: 10.3390/cells13181557] [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: 08/20/2024] [Revised: 09/12/2024] [Accepted: 09/15/2024] [Indexed: 09/28/2024] Open
Abstract
The relationship between tumor microenvironments (TMEs) of regional lymph node metastases (LNMs) and primary tumors in head and neck squamous cell carcinoma (HNSCC) remains unclear. This study compared tumor-infiltrating lymphocytes (TILs) and the immune phenotype (IP), characterized by spatial TIL distribution, between primary tumors and LNMs. Twenty-one HNSCC patients with regional LNM who received immune checkpoint inhibitors (ICIs) were included. A paired comparative analysis of TIL densities and IP between primary tumors and LNMs revealed no significant difference or correlation between TIL densities in primary tumors and LNMs. Their IPs were discordant in 12 patients (57.1%). Patients with high intratumoral TIL exhibited longer progression-free survival (PFS) than those with low intratumoral TIL in both primary tumors (median, 5.2 vs. 1.3 months, p = 0.003) and LNMs (median, 30.2 vs. 1.3 months, p = 0.012). Patients with inflamed IP exhibited longer PFS than those with non-inflamed IP in both primary tumors (median, 4.5 vs. 1.3 months, p = 0.043) and LNMs (median, 4.1 vs. 1.3 months, p = 0.037). Given the lack of correlation in TIL densities, the discrepancies in IP, and the predictive value of both TMEs, evaluating the TMEs of both primary tumors and LNMs may be beneficial for the precise use of ICIs in HNSCC. There was a significant discordance between the TME of primary tumors and LNMs, with implications in survival outcomes. Therefore, evaluating the TME of both the primary tumor and LNM could be beneficial for the precise use of ICIs in HNSCC.
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Affiliation(s)
- Dong Hyun Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea;
- Department of Translational Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Jong Seok Ahn
- Lunit Inc., Seoul 06241, Republic of Korea; (J.S.A.); (M.K.); (G.P.); (Y.L.); (S.H.); (C.-Y.O.)
| | - Mingu Kang
- Lunit Inc., Seoul 06241, Republic of Korea; (J.S.A.); (M.K.); (G.P.); (Y.L.); (S.H.); (C.-Y.O.)
| | - Gahee Park
- Lunit Inc., Seoul 06241, Republic of Korea; (J.S.A.); (M.K.); (G.P.); (Y.L.); (S.H.); (C.-Y.O.)
| | - Yoojoo Lim
- Lunit Inc., Seoul 06241, Republic of Korea; (J.S.A.); (M.K.); (G.P.); (Y.L.); (S.H.); (C.-Y.O.)
| | - Soohyun Hwang
- Lunit Inc., Seoul 06241, Republic of Korea; (J.S.A.); (M.K.); (G.P.); (Y.L.); (S.H.); (C.-Y.O.)
| | - Chan-Young Ock
- Lunit Inc., Seoul 06241, Republic of Korea; (J.S.A.); (M.K.); (G.P.); (Y.L.); (S.H.); (C.-Y.O.)
| | - Jiwon Koh
- Department of Pathology, Seoul National University Hospital, Seoul 03080, Republic of Korea (Y.K.J.); (K.C.J.)
- Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Eun-Jae Chung
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul 03080, Republic of Korea; (E.-J.C.); (S.-K.K.); (S.-H.A.)
| | - Seong-Keun Kwon
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul 03080, Republic of Korea; (E.-J.C.); (S.-K.K.); (S.-H.A.)
| | - Yoon Kyung Jeon
- Department of Pathology, Seoul National University Hospital, Seoul 03080, Republic of Korea (Y.K.J.); (K.C.J.)
- Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Kyeong Cheon Jung
- Department of Pathology, Seoul National University Hospital, Seoul 03080, Republic of Korea (Y.K.J.); (K.C.J.)
| | - Soon-Hyun Ahn
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul 03080, Republic of Korea; (E.-J.C.); (S.-K.K.); (S.-H.A.)
| | - Bhumsuk Keam
- Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea;
- Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
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Pouyiourou M, Mokry T, Feszler M, Teifke A, Kreft A, Krämer A. Cancer of unknown primary derived from regressed breast cancer. J Cancer Res Clin Oncol 2024; 150:229. [PMID: 38703270 PMCID: PMC11069480 DOI: 10.1007/s00432-024-05768-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 04/26/2024] [Indexed: 05/06/2024]
Affiliation(s)
- Maria Pouyiourou
- Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Theresa Mokry
- Department of Diagnostic and Interventional Radiology, University of Heidelberg, Heidelberg, Germany
| | - Maximilian Feszler
- Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Andrea Teifke
- Department of Diagnostic and Interventional Radiology, University of Mainz, Mainz, Germany
| | - Andreas Kreft
- Institute of Pathology, University of Mainz, Mainz, Germany
| | - Alwin Krämer
- Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
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6
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Ji P, He J. Prognostic value of pretreatment systemic immune-inflammation index in patients with endometrial cancer: a meta-analysis. Biomark Med 2024; 18:345-356. [PMID: 38623927 PMCID: PMC11218804 DOI: 10.2217/bmm-2023-0629] [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: 10/07/2023] [Accepted: 03/06/2024] [Indexed: 04/17/2024] Open
Abstract
Background: The present work focused on evaluating the systemic immune-inflammation index (SII) for its role in predicting endometrial cancer (EC) patient prognosis by meta-analysis. Methods: SII's role in predicting the prognosis of EC patients was analyzed by calculating combined hazard ratios (HRs) and 95% CIs. Results: As revealed by combined analysis, an increased SII predicted poor overall survival (HR = 2.01; 95% CI = 1.58-2.57; p < 0.001) as well as inferior progression-free survival (HR = 1.87; 95% CI = 1.36-2.58; p < 0.001) of EC. Conclusion: An increased SII score significantly predicted poor overall survival and progression-free survival in subjects with EC. The SII is suitable for predicting short- and long-term prognoses of patients with EC.
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Affiliation(s)
- Pengtian Ji
- Department of Oncological Radiotherapy, Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University, The Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, 313000, China
| | - Junjun He
- Clinical Laboratory, Huzhou Traditional Chinese Medicine Hospital Affiliated to Zhejiang Chinese Medical University, Huzhou, Zhejiang, China
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Chen X, Liu Z, Song J, Li J. Platelet-lymphocyte ratio as a predictor of lymph node metastasis in small bowel cancer. J Robot Surg 2024; 18:172. [PMID: 38613728 DOI: 10.1007/s11701-024-01915-9] [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: 02/22/2024] [Accepted: 03/18/2024] [Indexed: 04/15/2024]
Abstract
The purpose of this research was to investigate the potential predictive value of preoperative systemic inflammatory indexes in identifying lymph node metastasis among patients diagnosed with small bowel cancer. A retrospective analysis of clinical data was conducted on small bowel cancer patients who underwent surgical treatment at the gastrointestinal surgery department of our hospital between January 2010 and June 2021. Patients were divided into groups based on the presence or absence of lymph node metastasis as confirmed by postoperative pathological results. The study compared the differences in preoperative inflammatory indexes and clinical data between the two groups using single factor analysis and multifactorial Logistic regression analysis. Furthermore, a nomogram model for predicting lymph node metastasis in colorectal cancer was constructed using R software and internally validated. The study sample consisted of 140 small bowel cancer patients,postoperative pathology confirmed lymph node metastasis in 72 cases. Univariate analysis results indicated associations between preoperative inflammatory indexes and clinical data with lymph node metastasis in small bowel cancer. Multifactorial logistic regression analysis revealed that gender, PLR, number of lymph node dissection, and lymphovascular invasion independently influenced lymph node metastasis in small bowel cancer patients. The developed nomogram model demonstrated a C-index of 0.855 (95% CI 0.792-0.917), with a calibrated prediction curve closely resembling the ideal curve. An elevated PLR is an independent risk factor for LNM in patients with small bowel cancer.
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Affiliation(s)
- Xihao Chen
- Xi'an Medical University, Xi'an, 710068, China
- Department of Gastrointestinal Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Zhiyu Liu
- Xi'an Medical University, Xi'an, 710068, China
- Department of Gastrointestinal Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Jiawei Song
- Xi'an Medical University, Xi'an, 710068, China
- Department of Gastrointestinal Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Jipeng Li
- Department of Gastrointestinal Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
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Han EK, Woo JW, Suh KJ, Kim SH, Kim JH, Park SY. PD-L1 (SP142) Expression in Primary and Recurrent/Metastatic Triple-Negative Breast Cancers and Its Clinicopathological Significance. Cancer Res Treat 2024; 56:557-566. [PMID: 38097920 PMCID: PMC11016636 DOI: 10.4143/crt.2023.1025] [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: 09/11/2023] [Accepted: 12/11/2023] [Indexed: 04/13/2024] Open
Abstract
PURPOSE The programmed death-ligand 1 (PD-L1) SP142 assay identifies patients with triple-negative breast cancer (TNBC) who are most likely to respond to the anti-PD-L1 agent atezolizumab. We aimed to compare PD-L1 (SP142) expression between primary and recurrent/metastatic TNBCs and elucidate the clinicopathological features associated with its expression. MATERIALS AND METHODS Primary and recurrent/metastatic TNBCs tested with PD-L1 (SP142) were collected, and clinicopathological information of these cases was obtained through a review of slides and medical records. RESULTS PD-L1 (SP142) positivity was observed in 50.9% (144/283) of primary tumors and 37.8% (31/82) of recurrent/metastatic TNBCs with a significant difference. Recurrent or metastatic sites were associated with PD-L1 positivity, with high PD-L1 positivity in the lung, breast, and soft tissues, and low positivity in the bone, skin, liver, and brain. When comparing PD-L1 expression between primary and matched recurrent/metastatic TNBCs using 55 paired samples, 20 cases (36.4%) showed discordance; 10 cases revealed positive conversion, and another 10 cases revealed negative conversion during metastatic progression. In primary TNBCs, PD-L1 expression was associated with a higher histologic grade, lower T category, pushing border, and higher tumor-infiltrating lymphocyte infiltration. In survival analyses, PD-L1 positivity, especially high positivity, was found to be associated with favorable prognosis of patients. CONCLUSION PD-L1 (SP142) expression was lower in recurrent/metastatic TNBCs, and substantial cases showed discordance in its expression between primary and recurrent/metastatic sites, suggesting that multiple sites may need to be tested for PD-L1 (SP142) when considering atezolizumab therapy. PD-L1 (SP142)-positive TNBCs seems to be associated with favorable clinical outcomes.
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Affiliation(s)
- Eun Kyung Han
- Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Ji Won Woo
- Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Koung Jin Suh
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Se Hyun Kim
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Jee Hyun Kim
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - So Yeon Park
- Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
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Albarrán V, San Román M, Pozas J, Chamorro J, Rosero DI, Guerrero P, Calvo JC, González C, García de Quevedo C, Pérez de Aguado P, Moreno J, Cortés A, Soria A. Adoptive T cell therapy for solid tumors: current landscape and future challenges. Front Immunol 2024; 15:1352805. [PMID: 38550594 PMCID: PMC10972864 DOI: 10.3389/fimmu.2024.1352805] [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: 12/08/2023] [Accepted: 03/04/2024] [Indexed: 04/02/2024] Open
Abstract
Adoptive cell therapy (ACT) comprises different strategies to enhance the activity of T lymphocytes and other effector cells that orchestrate the antitumor immune response, including chimeric antigen receptor (CAR) T-cell therapy, T-cell receptor (TCR) gene-modified T cells, and therapy with tumor-infiltrating lymphocytes (TILs). The outstanding results of CAR-T cells in some hematologic malignancies have launched the investigation of ACT in patients with refractory solid malignancies. However, certain characteristics of solid tumors, such as their antigenic heterogeneity and immunosuppressive microenvironment, hamper the efficacy of antigen-targeted treatments. Other ACT modalities, such as TIL therapy, have emerged as promising new strategies. TIL therapy has shown safety and promising activity in certain immunogenic cancers, mainly advanced melanoma, with an exciting rationale for its combination with immune checkpoint inhibitors. However, the implementation of TIL therapy in clinical practice is hindered by several biological, logistic, and economic challenges. In this review, we aim to summarize the current knowledge, available clinical results, and potential areas of future research regarding the use of T cell therapy in patients with solid tumors.
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Affiliation(s)
- Víctor Albarrán
- Department of Medical Oncology, Ramon y Cajal University Hospital, Madrid, Spain
| | - María San Román
- Department of Medical Oncology, Ramon y Cajal University Hospital, Madrid, Spain
| | - Javier Pozas
- Department of Medical Oncology, The Royal Marsden Hospital, London, United Kingdom
| | - Jesús Chamorro
- Department of Medical Oncology, Ramon y Cajal University Hospital, Madrid, Spain
| | - Diana Isabel Rosero
- Department of Medical Oncology, Ramon y Cajal University Hospital, Madrid, Spain
| | - Patricia Guerrero
- Department of Medical Oncology, Ramon y Cajal University Hospital, Madrid, Spain
| | - Juan Carlos Calvo
- Department of Medical Oncology, Ramon y Cajal University Hospital, Madrid, Spain
| | - Carlos González
- Department of Medical Oncology, Ramon y Cajal University Hospital, Madrid, Spain
| | | | | | - Jaime Moreno
- Department of Medical Oncology, Ramon y Cajal University Hospital, Madrid, Spain
| | - Alfonso Cortés
- Department of Medical Oncology, Ramon y Cajal University Hospital, Madrid, Spain
| | - Ainara Soria
- Department of Medical Oncology, Ramon y Cajal University Hospital, Madrid, Spain
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10
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Jacobs C, Shah S, Lu WC, Ray H, Wang J, Hockaden N, Sandusky G, Nephew KP, Lu X, Cao S, Carpenter RL. HSF1 Inhibits Antitumor Immune Activity in Breast Cancer by Suppressing CCL5 to Block CD8+ T-cell Recruitment. Cancer Res 2024; 84:276-290. [PMID: 37890164 PMCID: PMC10790131 DOI: 10.1158/0008-5472.can-23-0902] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 08/23/2023] [Accepted: 10/24/2023] [Indexed: 10/29/2023]
Abstract
Heat shock factor 1 (HSF1) is a stress-responsive transcription factor that promotes cancer cell malignancy. To provide a better understanding of the biological processes regulated by HSF1, here we developed an HSF1 activity signature (HAS) and found that it was negatively associated with antitumor immune cells in breast tumors. Knockdown of HSF1 decreased breast tumor size and caused an influx of several antitumor immune cells, most notably CD8+ T cells. Depletion of CD8+ T cells rescued the reduction in growth of HSF1-deficient tumors, suggesting HSF1 prevents CD8+ T-cell influx to avoid immune-mediated tumor killing. HSF1 suppressed expression of CCL5, a chemokine for CD8+ T cells, and upregulation of CCL5 upon HSF1 loss significantly contributed to the recruitment of CD8+ T cells. These findings indicate that HSF1 suppresses antitumor immune activity by reducing CCL5 to limit CD8+ T-cell homing to breast tumors and prevent immune-mediated destruction, which has implications for the lack of success of immune modulatory therapies in breast cancer. SIGNIFICANCE The stress-responsive transcription factor HSF1 reduces CD8+ T-cell infiltration in breast tumors to prevent immune-mediated killing, indicating that cellular stress responses affect tumor-immune interactions and that targeting HSF1 could improve immunotherapies.
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Affiliation(s)
- Curteisha Jacobs
- Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana
| | - Sakhi Shah
- Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana
| | - Wen-Cheng Lu
- Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana
| | - Haimanti Ray
- Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana
| | - John Wang
- Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana
| | - Natasha Hockaden
- Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana
| | - George Sandusky
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, Indiana
- Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Kenneth P. Nephew
- Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, Indiana
- Department of Anatomy, Cell Biology & Physiology, Indiana University, Indianapolis, Indiana
| | - Xin Lu
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, Indiana
- Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana
| | - Sha Cao
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, Indiana
- Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, Indiana
| | - Richard L. Carpenter
- Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, Indiana
- Department of Biochemistry and Molecular Biology, Medical Sciences, Indiana University School of Medicine, Indianapolis, Indiana
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11
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Hao L, Dong J, Yu H, Chen J, Han X, Pan Y. Association between platelet-to-lymphocyte ratio and outcomes in HER2-positive advanced breast cancer patients treated with pyrotinib: a retrospective study. Transl Cancer Res 2023; 12:2726-2741. [PMID: 37969380 PMCID: PMC10643952 DOI: 10.21037/tcr-23-1078] [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: 06/25/2023] [Accepted: 09/13/2023] [Indexed: 11/17/2023]
Abstract
Background Peripheral blood biomarkers have been reported to be associated with the prognosis of breast cancer (BC) patients, but a few findings remain controversial. This study aimed to explore the correlation between peripheral blood indicators and treatment outcomes in human epidermal growth factor receptor 2 (HER2)-positive advanced BC patients treated with pyrotinib. Methods This was a retrospective cohort study including 156 HER2-positive advanced BC patients who treated with pyrotinib between March 2019 and May 2021. The baseline clinical characteristics including age, hormone receptor (HR) status, Ki-67, sites of metastasis, antitumor therapies and peripheral blood parameters including neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), monocyte to lymphocyte ratio (MLR), the product of neutrophil, platelet, and monocyte counts divided by lymphocyte count [pan-immune-inflammation value (PIV)] were collected. Tumor response was assessed every two cycles during treatment period. Follow-up was performed every 2 months to record survival status. All patients were followed up until death or time of data lock. Results Low PLR was associated with better disease control rate (P=0.005). Univariate analysis showed that high MLR (P=0.004), PLR (P=0.003), or PIV (P=0.02), low lymphocyte count (P=0.025), more than two metastatic sites (P<0.001), and presence of liver metastasis (P<0.001) or brain metastasis (P<0.001) were associated with poor progression-free survival (PFS). Multivariate analysis showed that only high PLR was an independent factor for poor PFS [hazard ratio =0.63; 95% confidence interval (CI): 0.41-0.97; P=0.038]. For overall survival (OS), univariate analysis showed that high NLR (P=0.001), MLR (P=0.005), PLR (P<0.001), or PIV (P=0.018), more than two metastatic sites (P=0.001), presence of liver metastasis (P=0.004) or brain metastasis (P=0.007), and pyrotinib monotherapy (P=0.036) were associated with worse OS. Multivariate analysis showed that PLR (hazard ratio =0.37; 95% CI: 0.14-0.94; P=0.037), number of metastatic sites (hazard ratio =2.84; 95% CI: 1.02-7.94; P=0.046) and treatment regimens (hazard ratio =0.15; 95% CI: 0.03-0.73; P=0.019) were independent factors. Conclusions High PLR is associated with poor treatment response and is an independent unfavorable prognostic factor in HER2-positive advanced BC patients treated with pyrotinib. The findings herein indicate that patients with higher PLR are less likely to benefit from pyrotinib-based therapy and may be helpful in identifying the effective population in clinical practice.
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Affiliation(s)
- Li Hao
- Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
| | - Jie Dong
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
| | - Haiyang Yu
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
| | - Jian Chen
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
| | - Xinghua Han
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
| | - Yueyin Pan
- Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
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12
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Kawahara N, Yamanaka S, Sugimoto S, Kamibayashi J, Nishikawa K, Kawaguchi R, Kimura F. The Prognosis Predictive Score around Neo Adjuvant Chemotherapy (PPSN) Improves Diagnostic Efficacy in Predicting the Prognosis of Epithelial Ovarian Cancer Patients. Cancers (Basel) 2023; 15:5062. [PMID: 37894429 PMCID: PMC10605019 DOI: 10.3390/cancers15205062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 10/07/2023] [Accepted: 10/13/2023] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND Recent studies have shown that pretreatment inflammatory responses can predict prognosis. However, no reports have analyzed the combined effect of the inflammatory response with pre-treatment and post-neo adjuvant chemotherapy (NACT). This retrospective study aims to identify factors predicting prognosis and create a novel predictive scoring system. METHODS The study was conducted at our institution between June 2006 and March 2020. Demographic and clinicopathological data were collected from patients with advanced epithelial ovarian cancer who underwent neoadjuvant chemotherapy after sample collection by laparoscopic or laparotomy surgery, followed by interval debulking surgery. We created a scoring system, called the Predictive Prognosis Score around NACT (PPSN), using factors extracted from a receiver operating characteristic curve analysis. Univariate and multivariate analyses were conducted to assess the efficacy of PPSN in predicting progression-free survival and overall survival. Kaplan-Meier and log-rank tests were used to compare the PFS or OS rate. RESULTS Our study included 72 patients, with a cut-off value of four for the scoring system. Our analysis showed that high PPSN (≥4) significantly predicts poor prognosis. Moreover, CD3+ and CD8+ tumor-infiltrating lymphocytes with low PPSN (<4) showed higher aggregation than those with high PPSN (≥4) cases. CONCLUSION Our study shows that PPSN could be a useful prognostic tool for advanced EOC patients who undergo NACT followed by IDS.
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Affiliation(s)
- Naoki Kawahara
- Department of Obstetrics and Gynecology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan; (S.Y.); (S.S.); (J.K.); (K.N.); (R.K.); (F.K.)
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13
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He X, Peng Y, He G, Ye H, Liu L, Zhou Q, Shi J, Fu S, Wang J, Zhou Z, Li W. Increased co-expression of PD1 and TIM3 is associated with poor prognosis and immune microenvironment heterogeneity in gallbladder cancer. J Transl Med 2023; 21:717. [PMID: 37828574 PMCID: PMC10571407 DOI: 10.1186/s12967-023-04589-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 10/03/2023] [Indexed: 10/14/2023] Open
Abstract
BACKGROUND The effectiveness of immune checkpoint inhibitors in treating gallbladder cancer (GBC) remains unsatisfactory. Recently, several new immune checkpoints have been identified. However, investigations exploring these immune checkpoints in GBC are limited. In this study, we aim to investigate the expression patterns and clinical implications of various immune checkpoints, and further characterize the spatial and quantitative heterogeneity of immune components in GBC. METHODS We employed single and multiplex immunohistochemistry to evaluate the expression of five immune checkpoint markers and four immune cell markers in the primary tumor core, hepatic invasion margin, and liver metastasis. Subsequently, we analyzed their interrelationships and their prognostic significance. RESULTS We observed a robust positive correlation between PD1/TIM3 expression in GBC (R = 0.614, P < 0.001). The co-expression of PD1/TIM3 exhibited a synergistic effect in predicting poor prognosis among postoperative GBC patients. Further analysis revealed that the prognostic significance of PD1/TIM3 was prominent in the subgroup with high infiltration of CD8 + T cells (P < 0.001). Multiplex immunohistochemistry reveals that PD1 + TIM3 + FOXP3 + cells constitute a significant proportion of FOXP3 + TILs in GBC tissue. Moreover, the co-high expression of PD1 and TIM3 is positively correlated with the accumulation of CD8 + TILs at the hepatic invasion margin. Lastly, our findings indicated reduced expression levels of immune checkpoints and diminished immune cell infiltration in liver metastases compared to primary tumors. CONCLUSIONS Increased co-expression of PD1/TIM3 is associated with poor prognosis in GBC patients and is related to the heterogeneity of immune microenvironment between GBC primary tumor and its hepatic invasion margin or liver metastases, which may be a potential target for future immunotherapy of GBC.
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Affiliation(s)
- Xing He
- Department of Biliary and Pancreatic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No.107 Yanjiang West Road, Yuexiu District, Guangzhou, 510120, Guangdong, People's Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Yaorong Peng
- Department of Biliary and Pancreatic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No.107 Yanjiang West Road, Yuexiu District, Guangzhou, 510120, Guangdong, People's Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Gui He
- Cellular & Molecular Diagnostics Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Huilin Ye
- Department of Biliary and Pancreatic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No.107 Yanjiang West Road, Yuexiu District, Guangzhou, 510120, Guangdong, People's Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Liqiang Liu
- Department of Biliary and Pancreatic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No.107 Yanjiang West Road, Yuexiu District, Guangzhou, 510120, Guangdong, People's Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Qixian Zhou
- Department of Biliary and Pancreatic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No.107 Yanjiang West Road, Yuexiu District, Guangzhou, 510120, Guangdong, People's Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Juanyi Shi
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Sha Fu
- Cellular & Molecular Diagnostics Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Jie Wang
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Zhenyu Zhou
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.
| | - Wenbin Li
- Department of Biliary and Pancreatic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No.107 Yanjiang West Road, Yuexiu District, Guangzhou, 510120, Guangdong, People's Republic of China.
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.
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Banerjee M, Devi Rajeswari V. A novel cross-communication of HIF-1α and HIF-2α with Wnt signaling in TNBC and influence of hypoxic microenvironment in the formation of an organ-on-chip model of breast cancer. Med Oncol 2023; 40:245. [PMID: 37454033 DOI: 10.1007/s12032-023-02112-8] [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: 04/30/2023] [Accepted: 07/01/2023] [Indexed: 07/18/2023]
Abstract
The microenvironment role is very important in cancer development. The epithelial-mesenchymal transition of the cancer cells depends upon specific signaling and microenvironmental conditions, such as hypoxic conditions. The crosstalk between hypoxia and Wnt signaling through some molecular mechanism in TNBC is related. Cross-communication between hypoxia and Wnt signaling in cancer cells is known, but the detailed mechanism in TNBC is unknown. This review includes the role of the hypoxia microenvironment in TNBC and the novel crosstalk of the Wnt signaling and hypoxia. When targeted, the new pathway and crosstalk link may be a solution for metastatic TNBC and chemoresistance. The microenvironment influences cancer's metastasis, which changes from person to person. Therefore, organ-on-a-chip is a very novel model to test the drugs clinically before going for human trials, focusing on personalized medications can be done. The effect of the hypoxia microenvironment on breast cancer stem cells is still unknown. Apart from all the published papers, this paper mainly focuses only on the hypoxic microenvironment and its association with the growth of TNBC. The medicines or small proteins, drugs, mimics, and inhibitors targeting wnt and hypoxia genes are consolidated in this review paper.
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Affiliation(s)
- Manosi Banerjee
- Department of Biomedical Science, School of Bioscience and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India
| | - V Devi Rajeswari
- Department of Biomedical Science, School of Bioscience and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India.
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15
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Chatziioannou E, Roßner J, Aung TN, Rimm DL, Niessner H, Keim U, Serna-Higuita LM, Bonzheim I, Kuhn Cuellar L, Westphal D, Steininger J, Meier F, Pop OT, Forchhammer S, Flatz L, Eigentler T, Garbe C, Röcken M, Amaral T, Sinnberg T. Deep learning-based scoring of tumour-infiltrating lymphocytes is prognostic in primary melanoma and predictive to PD-1 checkpoint inhibition in melanoma metastases. EBioMedicine 2023; 93:104644. [PMID: 37295047 PMCID: PMC10363450 DOI: 10.1016/j.ebiom.2023.104644] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 05/15/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023] Open
Abstract
BACKGROUND Recent advances in digital pathology have enabled accurate and standardised enumeration of tumour-infiltrating lymphocytes (TILs). Here, we aim to evaluate TILs as a percentage electronic TIL score (eTILs) and investigate its prognostic and predictive relevance in cutaneous melanoma. METHODS We included stage I to IV cutaneous melanoma patients and used hematoxylin-eosin-stained slides for TIL analysis. We assessed eTILs as a continuous and categorical variable using the published cut-off of 16.6% and applied Cox regression models to evaluate associations of eTILs with relapse-free, distant metastasis-free, and overall survival. We compared eTILs of the primaries with matched metastasis. Moreover, we assessed the predictive relevance of eTILs in therapy-naïve metastases according to the first-line therapy. FINDINGS We analysed 321 primary cutaneous melanomas and 191 metastatic samples. In simple Cox regression, tumour thickness (p < 0.0001), presence of ulceration (p = 0.0001) and eTILs ≤16.6% (p = 0.0012) were found to be significant unfavourable prognostic factors for RFS. In multiple Cox regression, eTILs ≤16.6% (p = 0.0161) remained significant and downgraded the current staging. Lower eTILs in the primary tissue was associated with unfavourable relapse-free (p = 0.0014) and distant metastasis-free survival (p = 0.0056). In multiple Cox regression adjusted for tumour thickness and ulceration, eTILs as continuous remained significant (p = 0.019). When comparing TILs in primary tissue and corresponding metastasis of the same patient, eTILs in metastases was lower than in primary melanomas (p < 0.0001). In therapy-naïve metastases, an eTILs >12.2% was associated with longer progression-free survival (p = 0.037) and melanoma-specific survival (p = 0.0038) in patients treated with anti-PD-1-based immunotherapy. In multiple Cox regression, lactate dehydrogenase (p < 0.0001) and eTILs ≤12.2% (p = 0.0130) were significantly associated with unfavourable melanoma-specific survival. INTERPRETATION Assessment of TILs is prognostic in primary melanoma samples, and the eTILs complements staging. In therapy-naïve metastases, eTILs ≤12.2% is predictive of unfavourable survival outcomes in patients receiving anti-PD-1-based therapy. FUNDING See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript.
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Affiliation(s)
- Eftychia Chatziioannou
- Department of Dermatology, University of Tübingen, Liebermeisterstr. 25, 72076 Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", Tübingen, Germany
| | - Jana Roßner
- Department of Dermatology, University of Heidelberg, Im Neuenheimer Feld 440, 69120 Heidelberg, Germany
| | - Thazin New Aung
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - David L Rimm
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Heike Niessner
- Department of Dermatology, University of Tübingen, Liebermeisterstr. 25, 72076 Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", Tübingen, Germany
| | - Ulrike Keim
- Department of Dermatology, University of Tübingen, Liebermeisterstr. 25, 72076 Tübingen, Germany
| | - Lina Maria Serna-Higuita
- Department of Clinical Epidemiology and Applied Biostatistics, Eberhard Karls University of Tübingen, 72076 Tübingen, Germany
| | - Irina Bonzheim
- Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen, 72076 Tübingen, Germany
| | - Luis Kuhn Cuellar
- Quantitative Biology Center (QBiC), University of Tübingen, Tübingen, Germany
| | - Dana Westphal
- Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Skin Cancer Center at the University Cancer Center and National Center for Tumor Diseases, Technical University Dresden, 01307 Dresden, Germany
| | - Julian Steininger
- Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Skin Cancer Center at the University Cancer Center and National Center for Tumor Diseases, Technical University Dresden, 01307 Dresden, Germany
| | - Friedegund Meier
- Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Skin Cancer Center at the University Cancer Center and National Center for Tumor Diseases, Technical University Dresden, 01307 Dresden, Germany
| | - Oltin Tiberiu Pop
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Stephan Forchhammer
- Department of Dermatology, University of Tübingen, Liebermeisterstr. 25, 72076 Tübingen, Germany
| | - Lukas Flatz
- Department of Dermatology, University of Tübingen, Liebermeisterstr. 25, 72076 Tübingen, Germany; Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Thomas Eigentler
- Department of Dermatology, Venereology and Allergology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Claus Garbe
- Department of Dermatology, University of Tübingen, Liebermeisterstr. 25, 72076 Tübingen, Germany
| | - Martin Röcken
- Department of Dermatology, University of Tübingen, Liebermeisterstr. 25, 72076 Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", Tübingen, Germany
| | - Teresa Amaral
- Department of Dermatology, University of Tübingen, Liebermeisterstr. 25, 72076 Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", Tübingen, Germany
| | - Tobias Sinnberg
- Department of Dermatology, University of Tübingen, Liebermeisterstr. 25, 72076 Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", Tübingen, Germany; Department of Dermatology, Venereology and Allergology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
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Sekino M, Iwadate M, Yamaya Y, Matsumoto Y, Suzuki S, Mizunuma H, Nakano K, Nakamura I, Suzuki S. Analysis of Expression of Programmed Cell Death Ligand 1 (PD-L1) and BRAFV600E Mutation in Thyroid Cancer. Cancers (Basel) 2023; 15:3449. [PMID: 37444559 DOI: 10.3390/cancers15133449] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 06/24/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
In thyroid cancer, it has been suggested that PD-L1 overexpression is associated with some clinicopathological factors and prognosis. The aim of this study is to characterize the expression of PD-L1, the presence of the BRAFV600E mutation, as well as cellular and humoral immunity in thyroid cancer, and to investigate the factors that predict the effectiveness of anti-PD-L1 antibody therapy. Blood samples were collected from 33 patients who were newly diagnosed with thyroid cancer after surgery or biopsy. PD-L1 expression, BRAFV600E mutation, and CD8+ expression were examined by immunohistological staining using clinical thyroid cancer specimens. With a PD-L1 staining cut-off value of 1%, 13 (39.4%) patients were classified as PD-L1 positive. Stimulation Index (SI) is an indicator of T cell activation. PD-L1 expression was significantly correlated with low SI level (p = 0.046). Moreover, BRAFV600E mutation was detected in 24 of the 33 (72.7%) patients, and was significantly associated with PD-L1 expression (p = 0.047). In addition, enhanced CD8+ expression was significantly associated with PD-L1 expression (p = 0.003). Multivariate analyses confirmed that high CRP levels (p = 0.039) were independently and significantly associated with poor progression-free survival. These findings suggest that elevated PD-L1 status can be a prognostic indicator for survival in patients with thyroid cancer when comprehensively assessed using the expression of CD8+, the presence of BRAFV600E mutation and the patient's immune status.
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Affiliation(s)
- Mizuki Sekino
- Department of Thyroid and Endocrinology, Fukushima Medical University, 1 Hikariga-oka, Fukushima City 960-1295, Japan
| | - Manabu Iwadate
- Department of Thyroid and Endocrinology, Fukushima Medical University, 1 Hikariga-oka, Fukushima City 960-1295, Japan
| | - Yukie Yamaya
- Department of Thyroid and Endocrinology, Fukushima Medical University, 1 Hikariga-oka, Fukushima City 960-1295, Japan
| | - Yoshiko Matsumoto
- Department of Thyroid and Endocrinology, Fukushima Medical University, 1 Hikariga-oka, Fukushima City 960-1295, Japan
| | - Satoshi Suzuki
- Department of Thyroid and Endocrinology, Fukushima Medical University, 1 Hikariga-oka, Fukushima City 960-1295, Japan
| | - Hiroshi Mizunuma
- Department of Thyroid and Endocrinology, Fukushima Medical University, 1 Hikariga-oka, Fukushima City 960-1295, Japan
| | - Keiichi Nakano
- Department of Thyroid and Endocrinology, Fukushima Medical University, 1 Hikariga-oka, Fukushima City 960-1295, Japan
| | - Izumi Nakamura
- Department of Thyroid and Endocrinology, Fukushima Medical University, 1 Hikariga-oka, Fukushima City 960-1295, Japan
| | - Shinichi Suzuki
- Department of Thyroid Treatment, Fukushima Medical University, 1 Hikariga-oka, Fukushima City 960-1295, Japan
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Sun GY, Zhang J, Wang BZ, Jing H, Fang H, Tang Y, Song YW, Jin J, Liu YP, Tang Y, Qi SN, Chen B, Lu NN, Li N, Li YX, Ying JM, Wang SL. The prognostic value of tumour-infiltrating lymphocytes, programmed cell death protein-1 and programmed cell death ligand-1 in Stage I-III triple-negative breast cancer. Br J Cancer 2023; 128:2044-2053. [PMID: 36966236 PMCID: PMC10205737 DOI: 10.1038/s41416-023-02218-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 02/09/2023] [Accepted: 02/23/2023] [Indexed: 03/27/2023] Open
Abstract
BACKGROUND Tumour-infiltrating lymphocytes (TILs) represent a robust biological prognostic biomarker in triple-negative breast cancer (TNBC); however, the contribution of different subsets of immune cells is unclear. We investigated the prognostic value of immune markers, including stromal TILs (sTILs), CD8+T and FOPX3+T cells, PD-1 and PD-L1 in non-metastatic TNBC. METHODS In total, 259 patients with Stage I-III TNBC were reviewed. The density of sTILs along with the presence of total (t), stromal (s), and intratumoral (i) CD8+T cells and FOPX3+T cells were evaluated by haematoxylin and eosin and immunohistochemical staining. Immunohistochemical staining of PD-1, PD-L1 was also conducted. RESULTS All immune markers were positively correlated with each other (P < 0.05). In the multivariate analysis, sTILs (P = 0.046), tCD8+T cells (P = 0.024), iCD8+T cells (P = 0.050) and PD-1 (P = 0.039) were identified as independent prognostic factors for disease-free survival (DFS). Further analysis showed that tCD8+T cells (P = 0.026), iCD8+T cells (P = 0.017) and PD-1 (P = 0.037) increased the prognostic value for DFS beyond that of the classic clinicopathological factors and sTILs. CONCLUSIONS In addition to sTILs, inclusion of tCD8+T, iCD8+T cells, or PD-1 may further refine the prognostic model for non-metastatic TNBC beyond that including classical factors alone.
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Affiliation(s)
- Guang-Yi Sun
- State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Jing Zhang
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Department of Pathology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, 350014, Fuzhou, China
| | - Bing-Zhi Wang
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Hao Jing
- State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Hui Fang
- State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Yu Tang
- State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Yong-Wen Song
- State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Jing Jin
- State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Yue-Ping Liu
- State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Yuan Tang
- State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Shu-Nan Qi
- State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Bo Chen
- State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Ning-Ning Lu
- State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Ning Li
- State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Ye-Xiong Li
- State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
| | - Jian-Ming Ying
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
| | - Shu-Lian Wang
- State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
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18
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Chew Minmin S, Bacotti A, Chen Y, Anders C, Sambade M, Deal AM, Trembath D, McKee MJ, Brogi E, Seidman AD. Impact of prior systemic therapy on lymphocytic infiltration in surgically resected breast cancer brain metastases. Breast Cancer Res Treat 2023; 199:99-107. [PMID: 36930347 PMCID: PMC10865424 DOI: 10.1007/s10549-023-06908-0] [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: 08/04/2022] [Accepted: 01/02/2023] [Indexed: 03/18/2023]
Abstract
PURPOSE Tumor-infiltrating lymphocytes (TILs) have been positively correlated with response to systemic therapy for triple-negative and HER2 + subtypes and improved clinical outcomes in early breast cancer (BC). Less is known about TILs in metastatic sites, particularly brain metastases (BM), where unique immune regulation governs stromal composition. Reactive glial cells actively participate in cytokine-mediated T cell stimulation. The impact of prior medical therapy (chemotherapy, endocrine, and HER2-targeted therapy) on the presence of TILs and gliosis in human breast cancer brain metastases (BCBM) has not been previously reported. METHODS We examined prior treatment data for 133 patients who underwent craniotomy for resection of BMs from the electronic medical record. The primary endpoint was overall survival (OS) from the time of BM diagnosis. We examined the relationship between prior systemic therapy exposure and the histologic features of gliosis, necrosis, hemorrhage, and lymphocyte infiltration (LI) in BCBMs resected at subsequent craniotomy in univariate analyses. RESULTS Complete treatment data were available for 123 patients. BCBM LI was identified in 35 of 116 (30%) patients who had received prior systemic treatment versus 5 of 7 (71.4%) who had not {significant by Fisher's exact test p = 0.045}. There were no statistically significant relationships between prior systemic therapy and the three other histologic variables examined. CONCLUSIONS This observation suggests that systemic therapy may interfere with the immune response to BCBMs and cause exhaustion of anti-tumor immunity. This motivates clinical investigation of strategies to enhance LI for therapeutic benefit to improve outcomes for patients with BCBMs.
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Affiliation(s)
- S Chew Minmin
- Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - A Bacotti
- Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Y Chen
- Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - C Anders
- Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC, USA
| | - M Sambade
- University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - A M Deal
- University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - D Trembath
- University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - M J McKee
- University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - E Brogi
- Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - A D Seidman
- Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Weill Cornell Medical College, New York, NY, USA.
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19
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Pierrard J, Van Ooteghem G, Van den Eynde M. Implications of the Organ-Specific Immune Environment for Immune Priming Effect of Radiotherapy in Metastatic Setting. Biomolecules 2023; 13:689. [PMID: 37189436 PMCID: PMC10136331 DOI: 10.3390/biom13040689] [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: 02/21/2023] [Revised: 04/07/2023] [Accepted: 04/17/2023] [Indexed: 05/17/2023] Open
Abstract
With the development of immune checkpoint inhibitors (ICIs), the tumour immune microenvironment (TIME) has been increasingly considered to improve cancer management. The TIME of metastatic lesions is strongly influenced by the underlying immune contexture of the organ in which they are located. The metastatic location itself appears to be an important prognostic factor in predicting outcomes after ICI treatment in cancer patients. Patients with liver metastases are less likely to respond to ICIs than patients with metastases in other organs, likely due to variations in the metastatic TIME. Combining additional treatment modalities is an option to overcome this resistance. Radiotherapy (RT) and ICIs have been investigated together as an option to treat various metastatic cancers. RT can induce a local and systemic immune reaction, which can promote the patient's response to ICIs. Here, we review the differential impact of the TIME according to metastatic location. We also explore how RT-induced TIME modifications could be modulated to improve outcomes of RT-ICI combinations.
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Affiliation(s)
- Julien Pierrard
- UCLouvain, Center of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institute de Recherche Experimentale et Clinique (IREC), 1200 Brussels, Belgium
- Radiation Oncology Department, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium
| | - Geneviève Van Ooteghem
- UCLouvain, Center of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institute de Recherche Experimentale et Clinique (IREC), 1200 Brussels, Belgium
- Radiation Oncology Department, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium
| | - Marc Van den Eynde
- UCLouvain, Center of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institute de Recherche Experimentale et Clinique (IREC), 1200 Brussels, Belgium
- Medical Oncology Department, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium
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20
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Gu Y, Hua Q, Li Z, Zhang X, Lou C, Zhang Y, Wang W, Cai P, Zhao J. Diagnostic value of combining preoperative inflammatory markers ratios with CA199 for patients with early-stage pancreatic cancer. BMC Cancer 2023; 23:227. [PMID: 36899319 PMCID: PMC9999638 DOI: 10.1186/s12885-023-10653-4] [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: 08/05/2022] [Accepted: 02/15/2023] [Indexed: 03/12/2023] Open
Abstract
BACKGROUND An early diagnosis of pancreatic cancer (PC) is extremely difficult because of the lack of sensitive liquid biopsy methods and effective biomarkers. We attempted to evaluate whether circulating inflammatory marker could complement CA199 for the detection of early-stage PC. METHODS We enrolled 430 patients with early-stage PC, 287 patients with other pancreatic tumors (OPT), and 401 healthy controls (HC). The patients and HC were randomly divided into a training set (n = 872) and two testing sets (n1 = 218, n2 = 28). The receiver operating characteristic (ROC) curves were investigated to evaluate the diagnostic performance of circulating inflammatory markers ratios, CA199, and combinations of the markers ratios in the training set, which would then be validated in the two testing sets. RESULTS Circulating fibrinogen, neutrophils, and monocytes in patients with PC were significantly higher while circulating albumin, prealbumin, lymphocytes, and platelets of patients with PC were significantly lower compared to those of HC and OPT (all P < 0.05). The fibrinogen-to-albumin (FAR), fibrinogen-to-prealbumin (FPR), neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR), monocyte-to-lymphocyte (MLR), and fibrinogen-to-lymphocyte (FLR) ratios were significantly higher while the prognostic nutrition index values (PNI) were lower in patients with PC than in HC and OPT (all P < 0.05). Combining the FAR, FPR, and FLR with CA199 exhibited the best diagnostic value for distinguishing patients with early-stage PC from HC with an area under the curve (AUC) of 0.964, and for distinguishing patients with early-stage PC from OPT with an AUC of 0.924 in the training sets. In the testing set, compared with HC, the combination markers had powerful efficiency for PC with an AUC 0.947 and AUC 0.942 when comparing PC with OPT. The AUC was 0.915 for the combination of CA199, FAR, FPR, and FLR for differentiating between patients with pancreatic head cancer (PHC) and other pancreatic head tumors (OPHT), and 0.894 for differentiating between patients with pancreatic body and tail cancer (PBTC) and other pancreatic body and tail tumors (OPBTT). CONCLUSION A combination of FAR, FPR, FLR, and CA199 may serve as a potential non-invasive biomarker for differentiating early-stage PC from HC and OPT, especially early-stage PHC.
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Affiliation(s)
- Yuanlong Gu
- Department of Interventional Oncology, Municipal Hospital Affiliated to Taizhou University, Taizhou, China.,Biotherapy Center, Harbin Medical University Cancer Hospital, Harbin, China
| | - Qianjin Hua
- Department of Interventional Oncology, Municipal Hospital Affiliated to Taizhou University, Taizhou, China
| | - Zhipeng Li
- School of Medicine, Taizhou University, Taizhou, 318000, Zhejiang, China
| | - Xingli Zhang
- Biotherapy Center, Harbin Medical University Cancer Hospital, Harbin, China
| | - Changjie Lou
- Biotherapy Center, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yangfen Zhang
- School of Medicine, Taizhou University, Taizhou, 318000, Zhejiang, China
| | - Wei Wang
- Department of Interventional Oncology, Municipal Hospital Affiliated to Taizhou University, Taizhou, China
| | - Peiyuan Cai
- Department of Interventional Oncology, Municipal Hospital Affiliated to Taizhou University, Taizhou, China
| | - Juan Zhao
- Biotherapy Center, Harbin Medical University Cancer Hospital, Harbin, China.
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21
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Dai M, Sun Q. Prognostic and clinicopathological significance of prognostic nutritional index (PNI) in patients with oral cancer: a meta-analysis. Aging (Albany NY) 2023; 15:1615-1627. [PMID: 36897190 PMCID: PMC10042682 DOI: 10.18632/aging.204576] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 02/13/2023] [Indexed: 03/09/2023]
Abstract
Accumulating literature has explored how prognostically significant the prognostic nutritional index (PNI) was for the oral carcinoma population, but with inconsistent findings. Therefore, we retrieved the most recent data and carried out this meta-analysis to comprehensively analyze the prognostic performance of pretreatment PNI in oral cancer. The electronic databases of PubMed, Embase, China National Knowledge Infrastructure (CNKI), Cochrane Library and Web of Science were fully retrieved. PNI's prognostic value for survival outcomes in oral carcinoma was assessed by estimating pooled hazard ratios (HRs) plus 95% confidence intervals (CIs). We examined the correlation of PNI with clinicopathological traits of oral carcinoma by utilizing the pooled odds ratios (ORs) plus 95% CIs. According to the pooled results of the present meta-analysis, which enrolled 10 studies involving 3,130 patients, for oral carcinoma suffers whose PNI was low, their disease-free survival (DFS) (HR=1.92, 95%CI=1.53-2.42, p<0.001) and overall survival (OS) (HR=2.44, 95%CI=1.45-4.12, p=0.001) would be inferior. Nonetheless, cancer-specific survival (CSS) was not linked significantly to PNI for the oral carcinoma population (HR=1.89, 95%CI=0.61-5.84, p=0.267). Significant associations of low PNI with TNM stages III-IV (OR=2.16, 95%CI=1.60-2.91, p<0.001) and age ≥ 65 years (OR=2.29, 95%CI=1.76-2.98, p<0.001) were found. As suggested by the present meta-analysis, a low PNI was linked to inferior DFS and OS among oral carcinoma patients. Oral cancer patients with low PNI may have high-risk of tumor progression. PNI could be served as a promising and effective index to predict prognosis in patients with oral cancer.
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Affiliation(s)
- Menglu Dai
- Clinical Laboratory, Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University, Huzhou 313000, Zhejiang, China
| | - Qijun Sun
- Stomatology Therapeutic Center, Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University, Huzhou 313000, Zhejiang, China
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22
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Licata L, Mariani M, Rossari F, Viale G, Notini G, Naldini MM, Bosi C, Piras M, Dugo M, Bianchini G. Tissue- and liquid biopsy-based biomarkers for immunotherapy in breast cancer. Breast 2023; 69:330-341. [PMID: 37003065 PMCID: PMC10070181 DOI: 10.1016/j.breast.2023.03.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 03/23/2023] [Accepted: 03/25/2023] [Indexed: 03/29/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy and now represent the mainstay of treatment for many tumor types, including triple-negative breast cancer and two agnostic registrations. However, despite impressive durable responses suggestive of an even curative potential in some cases, most patients receiving ICIs do not derive a substantial benefit, highlighting the need for more precise patient selection and stratification. The identification of predictive biomarkers of response to ICIs may play a pivotal role in optimizing the therapeutic use of such compounds. In this Review, we describe the current landscape of tissue and blood biomarkers that could serve as predictive factors for ICI treatment in breast cancer. The integration of these biomarkers in a "holistic" perspective aimed at developing comprehensive panels of multiple predictive factors will be a major step forward towards precision immune-oncology.
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Affiliation(s)
- Luca Licata
- Department of Medical Oncology, San Raffaele Hospital, Milan, Italy; School of Medicine and Surgery, Vita-Salute San Raffaele University, Milan, Italy
| | - Marco Mariani
- Department of Medical Oncology, San Raffaele Hospital, Milan, Italy; School of Medicine and Surgery, Vita-Salute San Raffaele University, Milan, Italy
| | - Federico Rossari
- Department of Medical Oncology, San Raffaele Hospital, Milan, Italy; School of Medicine and Surgery, Vita-Salute San Raffaele University, Milan, Italy; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giulia Viale
- Department of Medical Oncology, San Raffaele Hospital, Milan, Italy; School of Medicine and Surgery, Vita-Salute San Raffaele University, Milan, Italy
| | - Giulia Notini
- Department of Medical Oncology, San Raffaele Hospital, Milan, Italy; School of Medicine and Surgery, Vita-Salute San Raffaele University, Milan, Italy
| | - Matteo Maria Naldini
- Department of Medical Oncology, San Raffaele Hospital, Milan, Italy; School of Medicine and Surgery, Vita-Salute San Raffaele University, Milan, Italy; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Carlo Bosi
- Department of Medical Oncology, San Raffaele Hospital, Milan, Italy; School of Medicine and Surgery, Vita-Salute San Raffaele University, Milan, Italy
| | - Marta Piras
- Department of Medical Oncology, San Raffaele Hospital, Milan, Italy
| | - Matteo Dugo
- Department of Medical Oncology, San Raffaele Hospital, Milan, Italy; School of Medicine and Surgery, Vita-Salute San Raffaele University, Milan, Italy
| | - Giampaolo Bianchini
- Department of Medical Oncology, San Raffaele Hospital, Milan, Italy; School of Medicine and Surgery, Vita-Salute San Raffaele University, Milan, Italy.
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23
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Mutka M, Joensuu K, Eray M, Heikkilä P. Quantities of CD3+, CD8+ and CD56+ lymphocytes decline in breast cancer recurrences while CD4+ remain similar. Diagn Pathol 2023; 18:3. [PMID: 36627701 PMCID: PMC9830729 DOI: 10.1186/s13000-022-01278-5] [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: 08/12/2022] [Accepted: 12/19/2022] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Much is known about tumor infiltrating lymphocytes (Tils) in primary breast cancer, as this has been the focus of much research in recent years, but regarding recurrent breast cancer, only few studies have been done. Our aim was to compare the quantities of Tils in primary breast carcinomas and their corresponding recurrences and to analyze the differences in the tumor Tils compositions in correlations with recurrence-free times and the clinicopathology of the tumor. METHODS One hundred thirty-seven breast cancer patients self-paired for primary- tumor-recurrence were divided into three groups based on the length of the recurrence-free interval. H&E-staining and immunohistochemical staining with antiCD3, antiCD4, antiCD8 and antiCD56 were performed. Differences in Tils between primaries and recurrences, between the recurrence-free interval groups, and between different clinicopathologic parameters were statistically analyzed. RESULTS Fewer stromal CD3+, CD8+ and CD56+ lymphocytes were found at recurrences compared to the primaries. No significant change in the percentage of CD4+ stromal lymphocytes. ER-negative primaries, PR-negative or HER2-positive tumors had more Tils in some subgroups. Ductal primaries had more Tils than lobular primaries and G3 tumors had more Tils than lower-grade tumors. The corresponding differences at recurrences could either not be detected or they were reversed. The fastest recurring group had generally more Tils than the slower groups. CONCLUSIONS CD4+ cell numbers did not decline from primary to recurrence in contrast to all other subclasses of lymphocytes. The proportion of CD4+ cells was higher in recurrences than in primaries. Tumors with a higher grade and proliferation rate had higher percentages of Tils. HER2+ and hormone receptor negative tumors tended to have higher Tils scores. In recurrences these differences were not seen or they were reversed.
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Affiliation(s)
- Minna Mutka
- grid.7737.40000 0004 0410 2071Department of Pathology, HUSLAB, Helsinki University Hospital and University of Helsinki, FIN-00290 Helsinki, Finland
| | - Kristiina Joensuu
- grid.7737.40000 0004 0410 2071University of Helsinki, FIN-00290 Helsinki, Finland
| | - Mine Eray
- grid.7737.40000 0004 0410 2071Department of Pathology, HUSLAB, Helsinki University Hospital and University of Helsinki, FIN-00290 Helsinki, Finland
| | - Päivi Heikkilä
- grid.7737.40000 0004 0410 2071Department of Pathology, HUSLAB, Helsinki University Hospital and University of Helsinki, FIN-00290 Helsinki, Finland
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24
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Schreier A, Zappasodi R, Serganova I, Brown KA, Demaria S, Andreopoulou E. Facts and Perspectives: Implications of tumor glycolysis on immunotherapy response in triple negative breast cancer. Front Oncol 2023; 12:1061789. [PMID: 36703796 PMCID: PMC9872136 DOI: 10.3389/fonc.2022.1061789] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 11/17/2022] [Indexed: 01/11/2023] Open
Abstract
Triple negative breast cancer (TNBC) is an aggressive disease that is difficult to treat and portends a poor prognosis in many patients. Recent efforts to implement immune checkpoint inhibitors into the treatment landscape of TNBC have led to improved outcomes in a subset of patients both in the early stage and metastatic settings. However, a large portion of patients with TNBC remain resistant to immune checkpoint inhibitors and have limited treatment options beyond cytotoxic chemotherapy. The interplay between the anti-tumor immune response and tumor metabolism contributes to immunotherapy response in the preclinical setting, and likely in the clinical setting as well. Specifically, tumor glycolysis and lactate production influence the tumor immune microenvironment through creation of metabolic competition with infiltrating immune cells, which impacts response to immune checkpoint blockade. In this review, we will focus on how glucose metabolism within TNBC tumors influences the response to immune checkpoint blockade and potential ways of harnessing this information to improve clinical outcomes.
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Affiliation(s)
- Ashley Schreier
- Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY, United States
| | - Roberta Zappasodi
- Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, United States,Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, United States,Parker Institute for Cancer Immunotherapy, San Francisco, CA, United States
| | - Inna Serganova
- Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, United States,Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Kristy A. Brown
- Department of Medicine, Weill Cornell Medicine, New York, NY, United States
| | - Sandra Demaria
- Department of Radiation Oncology and Department of Pathology, Weill Cornell Medicine, New York, NY, United States
| | - Eleni Andreopoulou
- Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY, United States,*Correspondence: Eleni Andreopoulou,
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25
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Yamada M, Tanaka K, Yamasaki M, Yamashita K, Makino T, Saito T, Takahashi T, Kurokawa Y, Motoori M, Kimura Y, Nakajima K, Eguchi H, Doki Y. Neutrophil-to-lymphocyte ratio after neoadjuvant chemotherapy as an independent prognostic factor in patients with esophageal squamous cell carcinoma. Oncol Lett 2022; 25:58. [PMID: 36644140 PMCID: PMC9827446 DOI: 10.3892/ol.2022.13644] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 10/19/2022] [Indexed: 01/17/2023] Open
Abstract
Studies have shown that neoadjuvant chemotherapy (NAC) followed by surgical resection improves the survival of patients with esophageal squamous cell carcinoma (ESCC), and that the neutrophil-to-lymphocyte ratio (NLR) nay be a prognostic biomarker in various types of cancer. Despite the noTable changes in the tumor and its microenvironment during NAC, it remains unclear how the NLR changes and which values (before or after NAC) best predict prognosis. The present study aimed to analyze changes in the NLR before and after NAC, and to determine which was a better prognostic factor. This study retrospectively analyzed 338 consecutive patients with ESCC who received NAC followed by curative resection. NLRs before (pre-NLR) and after (post-NLR) NAC were calculated, after which the impact of NAC on NLR, overall survival (OS) and recurrence-free survival (RFS), as well as the relationship between hematological toxicities and NLR, was evaluated. Cutoff values for pre- and post-NLR were 3.7 and 2.5, respectively. Patients with high post-NLR had a worse OS (P=0.0001) and 3-year RFS (P=0.03) than those with low post-NLR. Multivariate analysis identified high post-NLR, pN1 and clinical response as independent prognostic factors. In conclusion, post-NLR was revealed as a better prognostic factor than pre-NLR for patients receiving NAC followed by surgical resection.
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Affiliation(s)
- Moyuru Yamada
- Department of Gastroenterological Surgery, Osaka University, Suita, Osaka 565-0871, Japan
| | - Koji Tanaka
- Department of Gastroenterological Surgery, Osaka University, Suita, Osaka 565-0871, Japan,Correspondence to: Dr Koji Tanaka, Department of Gastroenterological Surgery, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan, E-mail:
| | - Makoto Yamasaki
- Department of Gastroenterological Surgery, Osaka University, Suita, Osaka 565-0871, Japan
| | - Kotaro Yamashita
- Department of Gastroenterological Surgery, Osaka University, Suita, Osaka 565-0871, Japan
| | - Tomoki Makino
- Department of Gastroenterological Surgery, Osaka University, Suita, Osaka 565-0871, Japan
| | - Takuro Saito
- Department of Gastroenterological Surgery, Osaka University, Suita, Osaka 565-0871, Japan
| | - Tsuyoshi Takahashi
- Department of Gastroenterological Surgery, Osaka University, Suita, Osaka 565-0871, Japan
| | - Yukinori Kurokawa
- Department of Gastroenterological Surgery, Osaka University, Suita, Osaka 565-0871, Japan
| | - Masaaki Motoori
- Department of Surgery, Osaka General Medical Center, Osaka 558-8558, Japan
| | - Yutaka Kimura
- Department of Surgery, Kindai University Nara Hospital, Ikoma, Nara 630-0293, Japan
| | - Kiyokazu Nakajima
- Department of Gastroenterological Surgery, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University, Suita, Osaka 565-0871, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Osaka University, Suita, Osaka 565-0871, Japan
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26
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He Y, Zhou H, Huang X, Qu Y, Wang Y, Pei W, Zhang R, Chen S, You H. Infiltration of LPAR5 + macrophages in osteosarcoma tumor microenvironment predicts better outcomes. Front Immunol 2022; 13:909932. [PMID: 36591220 PMCID: PMC9797602 DOI: 10.3389/fimmu.2022.909932] [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: 03/31/2022] [Accepted: 12/01/2022] [Indexed: 12/23/2022] Open
Abstract
Introduction Tumor microenvironment (TME) has been shown to be extensively involved in tumor development. However, the dynamic change of TME components and their effects are still unclear. Here, we attempted to identify TME-related genes that could help predict survival and may be potential therapeutic targets. Methods Data was collected from UCSC Xena and GEO database. ESTIMATE and CIBERSORT algorithms were applied to estimate the components and the proportions of TIICs in TME. We analyzed the gene expression differences of immune components and stromal components, respectively, and finally got the overlapped DEGs. Through protein-protein interaction (PPI) network and univariate Cox regression analysis based on shared DEGs, we screened out and validated the TME-related genes. Focusing on this gene, we analyzed the expression and prognostic value of this gene, and investigated its relationship with immune cells by correlation analysis, single cell analysis, immunohistochemistry and immunofluorescence analysis. Results Through a series analysis, we found that the proportion of immune and stromal components was an important prognostic factor, and screened out a key gene, LPAR5, which was highly correlated with prognosis and metastasis. And the expression of LPAR5 was positively correlated with immune cells, especially macrophages, indicating LPAR5+ macrophages played an important role in tumor microenvironment of osteosarcoma. Meanwhile, the genes in LPAR5 high expression group were enriched in immune-related activities and pathways, and differentially expressed genes between LPAR5+ macrophages and LPAR5- macrophages were enriched in the biological processes associated with phagocytosis and antigen presentation. What' more, we found that LPAR5 was mainly expressed in TME, and high LPAR5 expression predicting a better prognosis. Conclusion We identified a TME-related gene, LPAR5, which is a promising indicator for TME remodeling in osteosarcoma. Particularly, LPAR5+ macrophages might have great potential to be a prognostic factor and therapeutic target for osteosarcoma.
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Affiliation(s)
- Yi He
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Haiting Zhou
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaojian Huang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yunkun Qu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yingguang Wang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wenbin Pei
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Rui Zhang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Sheng Chen
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hongbo You
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China,*Correspondence: Hongbo You,
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Zhao Q, Dong L, Liang H, Pang K, Wang P, Ge R, Li T, Jiang S, Chu Y. Evaluation of multiple biological indicators for combined diagnosis of gastric cancer: A retrospective analysis. Medicine (Baltimore) 2022; 101:e31904. [PMID: 36451446 PMCID: PMC9704904 DOI: 10.1097/md.0000000000031878] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
To assess carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), platelet distribution width (PDW), neutrophil-to-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR) for gastric cancer's (GC) diagnostic efficiency, and the use of receiver operating characteristic curves (ROC) combined with logistic regression to evaluate multi-index combination's diagnostic value of GC. 773 GC patients' clinical data were retrospectively collected in the Weihai Municipal Hospital, affiliated hospital of Shandong University from April 2018 to May 2021, and selected 2368 healthy physical examination patients during the same period as the control group. A total of 3141 samples was included in this study, including 773 cases in the GC group and 2368 cases in the healthy physical examination group. The results of the overall comparison between groups showed that apart from gender, the age differences, CEA, CA19-9, PDW, NLR, and PLR were statistically significant (P < .001). Spearman ranks correlation analysis's results showed that CA19-9, CEA, PLR, and NLR were correlated with GC patients' clinical-stage positively, and the correlation coefficients r was 0.249, 0.280, 0.252, 0.262 (all P < .001), and PDW was correlated with the clinical stage negatively (r = -0.186, P < .001). The ROC curve analysis results of CEA, CA19-9, PDW, NLR and PLR showed that CEA's diagnostic cutoff value for GC was 3.175 (area under the curve [AUC] = 0.631, 95% CI: 0.606-0.655, P < .001), the CA19-9's diagnostic cutoff value is 19.640 (AUC = 0.589, 95% CI: 0.563-0.615, P < .001), PDW's diagnostic cutoff value is 15.750 (AUC = 0.799, 95% CI: 0.778-0.820, P < .001), NLR's diagnostic cutoff value was 2.162 (AUC = 0.699, 95% CI: 0.675-0.721, P < .001), and PLR's diagnostic cutoff value was 149.540 (AUC = 0.709, 95% CI: 0.688-0.732, P < .001). The area under the ROC curve for the combined diagnosis of GC with 5 indicators was 0.877 (95% CI: 0.860-0.894, P < .001), which was better than a single indicator (P < .05). The diagnostic efficiency of combined detection of CEA, CA19-9, PDW, NLR, and PLR is better than that of single index detection alone, which can reduce the misdiagnosis rate of GC effectively.
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Affiliation(s)
- Qinfu Zhao
- Department of Gastroenterology, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong Province, China
| | - Luying Dong
- Department of Physical Examination, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong Province, China
| | - Heye Liang
- Department of Gastroenterology, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong Province, China
| | - Kai Pang
- Operation Management Section, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong Province, China
| | - Ping Wang
- Operation Management Section, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong Province, China
| | - Ruiyin Ge
- Department of Gastroenterology, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong Province, China
| | - Tian Li
- Department of Gastroenterology, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong Province, China
| | - Shuyi Jiang
- Department of Gastroenterology, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong Province, China
| | - Yanliu Chu
- Department of Gastroenterology, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong Province, China
- * Correspondence: Yanliu Chu, Department of Gastroenterology, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai 264200, China (e-mail:)
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Giannoudis A, Varešlija D, Sharma V, Zakaria R, Platt-Higgins A, Rudland P, Jenkinson M, Young L, Palmieri C. Characterisation of the immune microenvironment of primary breast cancer and brain metastasis reveals depleted T-cell response associated to ARG2 expression. ESMO Open 2022; 7:100636. [PMID: 36423363 PMCID: PMC9808462 DOI: 10.1016/j.esmoop.2022.100636] [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: 07/07/2022] [Revised: 10/11/2022] [Accepted: 10/15/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Immune checkpoint inhibition is an established treatment in programmed death-ligand 1 (PD-L1)-positive metastatic triple-negative (TN) breast cancer (BC). However, the immune landscape of breast cancer brain metastasis (BCBM) remains poorly defined. MATERIALS AND METHODS The tumour-infiltrating lymphocytes (TILs) and the messenger RNA (mRNA) levels of 770 immune-related genes (NanoString™, nCounter™ Immuno-oncology IO360) were assessed in primary BCs and BCBMs. The prognostic role of ARG2 transcripts and protein expression in primary BCs and its association with outcome was determined. RESULTS There was a significant reduction of TILs in the BCBMs in comparison to primary BCs. 11.5% of BCs presented a high immune infiltrate (hot), 46.2% were altered (immunosuppressed/excluded) and 34.6% were cold (no/low immune infiltrate). 3.8% of BCBMs were hot, 23.1% altered and 73.1% cold. One hundred and twelve immune-related genes including PD-L1 and CTLA4 were decreased in BCBM compared to the primary BCs (false discovery rate <0.01, log2 fold-change >1.5). These genes are involved in matrix remodelling and metastasis, cytokine-chemokine signalling, lymphoid compartment, antigen presentation and immune cell adhesion and migration. Immuno-modulators such as PD-L1 (CD274), CTLA4, TIGIT and CD276 (B7H3) were decreased in BCBMs. However, PD-L1 and CTLA4 expression was significantly higher in TN BCBMs (P = 0.01), with CTLA4 expression also high in human epidermal growth factor receptor 2-positive (P < 0.01) compared to estrogen receptor-positive BCBMs. ARG2 was one of four genes up-regulated in BCBMs. High ARG2 mRNA expression in primary BCs was associated with worse distant metastasis-free survival (P = 0.038), while ARG2 protein expression was associated with worse breast-brain metastasis-free (P = 0.027) and overall survival (P = 0.019). High transcript levels of ARG2 correlated to low levels of cytotoxic and T cells in both BC and BCBM (P < 0.01). CONCLUSION This study highlights the immunological differences between primary BCs and BCBMs and the potential importance of ARG2 expression in T-cell depletion and clinical outcome.
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Affiliation(s)
- A. Giannoudis
- Institute of Systems, Molecular and Integrative Biology, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
| | - D. Varešlija
- The School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - V. Sharma
- Institute of Systems, Molecular and Integrative Biology, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK,Department of Pathology, Royal Liverpool University Hospital NHS Trust, Liverpool, UK
| | - R. Zakaria
- Institute of Systems, Molecular and Integrative Biology, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK,Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Liverpool, UK
| | - A. Platt-Higgins
- Institute of Systems, Molecular and Integrative Biology, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
| | - P.S. Rudland
- Institute of Systems, Molecular and Integrative Biology, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
| | - M.D. Jenkinson
- Institute of Systems, Molecular and Integrative Biology, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK,Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Liverpool, UK
| | - L.S. Young
- Endocrine Oncology Research Group, Department of Surgery, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - C. Palmieri
- Institute of Systems, Molecular and Integrative Biology, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK,The Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, UK,Correspondence to: Prof. Carlo Palmieri, University of Liverpool, Institute of Systems, Molecular and Integrative Biology, Molecular and Clinical Cancer Medicine, Sherrington Building, Ashton Street, Liverpool, L69 3GE, UK. Tel: +44 151 7949813 @cancermedic
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Peng X, Wang X, Hua L, Yang R. Prognostic and Clinical Value of the Systemic Immune-Inflammation Index in Biliary Tract Cancer: A Meta-Analysis. J Immunol Res 2022; 2022:6988489. [PMID: 36438200 PMCID: PMC9691295 DOI: 10.1155/2022/6988489] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 09/26/2022] [Accepted: 10/18/2022] [Indexed: 08/10/2023] Open
Abstract
Previous studies that explored the prognostic and clinical value of the systemic immune-inflammation index (SII) in biliary tract cancer (BTC) had inconsistent results. We conducted this meta-analysis to evaluate the prognostic and clinicopathological role of the SII in biliary tract cancer. Combined analysis demonstrated that high SII levels had worse overall survival (HR = 1.92, 95% CI: 1.66-2.21, p < 0.001) than those with low SII levels. And an elevated SII was associated with lymph node metastasis (OR = 1.44, 95% CI = 1.18-1.76; p < 0.001), TNM stage (OR = 1.49, 95% CI = 1.05-2.13; p = 0.028), and vascular invasion (OR = 1.49, 95% CI = 1.05-2.13; p = 0.028). Conversely, no significant association between a high SII and sex or tumor differentiation was found. Our findings demonstrate that high SII levels were correlated with unfavorable survival outcomes among patients with BTC and that they were also correlated with some higher malignancy features of BTC.
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Affiliation(s)
- Xiulan Peng
- Department of Oncology, The Second Affiliated Hospital of Jianghan University, the Fifth Hospital of Wuhan, Wuhan, Hubei 430000, China
| | - Xia Wang
- Department of Pharmacy, The Second Affiliated Hospital of Jianghan University, the Fifth Hospital of Wuhan, Wuhan, Hubei 430000, China
| | - Li Hua
- Department of General Medicine, The Second Affiliated Hospital of Jianghan University, the Fifth Hospital of Wuhan, Wuhan, Hubei province, 430050, China
| | - Rui Yang
- Department of Vascular Surgery, The Second Affiliated Hospital of Jianghan University, the Fifth Hospital of Wuhan, Wuhan, Hubei 430000, China
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Peterko AC, Rajković-Molek K, Gulić T, Vujaklija DV, Lovasić IB, Lovasić F, Mustać E, Avirović M. HSP70 In triple negative breast cancer: Prognostic value and clinical significance. Pathol Res Pract 2022; 238:154127. [PMID: 36174439 DOI: 10.1016/j.prp.2022.154127] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 09/10/2022] [Accepted: 09/13/2022] [Indexed: 12/01/2022]
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) has the worst prognosis and the highest immunogenic potential of all breast cancer subtypes. It is characterized by a lack of estrogen and progesterone receptors as well as HER2. A major component of the tumor microenvironment (TME) of TNBC is tumor-infiltrating lymphocytes (TILs). A chaperone heat shock protein 70 (HSP70) is involved in several pathways that enable tumour growth and progression, as well as in immune modulation. METHODS Immunohistochemical analysis of HSP70 expression in immune cells, as well as expression of immunosuppressive markers CTLA4 and PD-L1 and major TILs components: CD8, CD4 and Tregs were analyzed in the superficial and deep tumor layer of primary TNBC and compared with established clinicopathological parameters. Clinical data and surgical tissue samples from 68 TNBC patients who underwent initial surgery were included in the analysis and 36 control samples from benign breast tissue biopsies. RESULTS A higher expression of TILs, CD4, CD8 and PD-L1 was found in the invasive tumor front (ITF), as compared to the tumor center (TC) (p < 0001). HSP70 positive immune cells (HSP70(+) IC) in TC were associated with adverse clinical and pathological markers: higher stage of disease (P = 0.013), higher grade (P = 0.05) and a higher pN status (P < 0.001). In addition, higher expression of HSP70(+) IC from TC was correlated with the higher expression of FOXP3(+)T cells both in ITF (N = 61, rho=0.42, p < 0.001) and in metastatic tissue from the draining lymph nodes (N = 13, rho=0.61, P = 0.026). CONCLUSION Correlations between HSP70 immune cells expression and individual TILs components support the hypothesis of its active role in inducing immunosuppression and tumor progression. Routine determination of HSP70 expression, in immune cells of TC, may be of added value in the clinical decision-making process concerning axillary surgery.
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Affiliation(s)
- Ana Car Peterko
- Clinical Hospital Center Rijeka, Department of General Surgery and Surgical Oncology, Rijeka, Croatia
| | - Koraljka Rajković-Molek
- Clinical Hospital Center Rijeka, Clinical Department of Pathology and Cytology, Rijeka, Croatia.
| | - Tamara Gulić
- University of Rijeka, Faculty of Medicine, Department of Physiology Immunology and Pathophysiology, Rijeka, Croatia
| | | | - Ingrid Belac Lovasić
- Clinical Hospital Center Rijeka, Clinical Department of Radiotherapy and Oncology, Rijeka, Croatia
| | - Franjo Lovasić
- Clinical Hospital Center Rijeka, Department of General Surgery and Surgical Oncology, Rijeka, Croatia
| | - Elvira Mustać
- Clinical Hospital Center Rijeka, Clinical Department of Pathology and Cytology, Rijeka, Croatia
| | - Manuela Avirović
- Clinical Hospital Center Rijeka, Clinical Department of Pathology and Cytology, Rijeka, Croatia; University of Rijeka, Faculty of Medicine, Department of Pathology, Rijeka, Croatia
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Hurvitz SA, Bachelot T, Bianchini G, Harbeck N, Loi S, Park YH, Prat A, Gilham L, Boulet T, Gochitashvili N, Monturus E, Lambertini C, Nyawira B, Knott A, Restuccia E, Schmid P. ASTEFANIA: adjuvant ado-trastuzumab emtansine and atezolizumab for high-risk, HER2-positive breast cancer. Future Oncol 2022; 18:3563-3572. [PMID: 36382554 DOI: 10.2217/fon-2022-0485] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
There is a strong rationale for combining HER2-targeted therapies with cancer immunotherapy to increase efficacy in breast cancer, particularly in the early-stage setting, where the immune system has not been weakened by heavy pretreatment. ASTEFANIA aims to evaluate the efficacy of adjuvant atezolizumab in combination with ado-trastuzumab emtansine in patients with high-risk, HER2-positive early breast cancer and residual disease following HER2-based neoadjuvant therapy. Eligible patients will be randomized to receive ado-trastuzumab emtansine in combination with either atezolizumab or placebo for 14 cycles within 12 weeks of primary surgery. The primary outcome is invasive disease-free survival and secondary outcomes include additional efficacy end points, safety and pharmacokinetics. The study plans to enroll 1700 patients across 32 counties. Clinical Trial Registration: NCT04873362 (ClinicalTrials.gov).
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Affiliation(s)
- Sara A Hurvitz
- University of California Los Angeles/Jonsson Comprehensive Cancer Centre (UCLA/JCCC), 10833 Le Conte Ave., Los Angeles, CA 900024, USA
| | - Thomas Bachelot
- Centre Léon Bérard, 28 Prom. Léa et Napoléon Bullukian, 69008, Lyon, France
| | | | - Nadia Harbeck
- Department of Gynecology & Obstetrics & CCC Munich, Breast Center, LMU University Hospital, Marchioninistraße 15, 81377, Munich, Germany
| | - Sherene Loi
- Division of Cancer Research, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria, 3000, Australia
- The Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Grattan Street, Parkville, Victoria, 3010, Australia
| | - Yeon Hee Park
- Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul, South Korea
| | - Aleix Prat
- Hospital Clínic Barcelona, C. de Villarroel, 170, 08036, Barcelona, Spain
| | | | - Thomas Boulet
- F.Hoffmann-La Roche Ltd, Gartenstrasse 9, CH-4052, Basel, Switzerland
| | - Nino Gochitashvili
- Roche Products Limited, Hexagon Place, Shire Park, Falcon Way, Welwyn Garden City, AL7 1TW, UK
| | | | - Chiara Lambertini
- F.Hoffmann-La Roche Ltd, Gartenstrasse 9, CH-4052, Basel, Switzerland
| | - Beatrice Nyawira
- F.Hoffmann-La Roche Ltd, Gartenstrasse 9, CH-4052, Basel, Switzerland
| | - Adam Knott
- Roche Products Limited, Hexagon Place, Shire Park, Falcon Way, Welwyn Garden City, AL7 1TW, UK
| | | | - Peter Schmid
- Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 5PZ, UK
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Yang G, Lu T, Weisenberger DJ, Liang G. The Multi-Omic Landscape of Primary Breast Tumors and Their Metastases: Expanding the Efficacy of Actionable Therapeutic Targets. Genes (Basel) 2022; 13:1555. [PMID: 36140723 PMCID: PMC9498783 DOI: 10.3390/genes13091555] [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: 06/29/2022] [Revised: 08/08/2022] [Accepted: 08/23/2022] [Indexed: 12/02/2022] Open
Abstract
Breast cancer (BC) mortality is almost exclusively due to metastasis, which is the least understood aspect of cancer biology and represents a significant clinical challenge. Although we have witnessed tremendous advancements in the treatment for metastatic breast cancer (mBC), treatment resistance inevitably occurs in most patients. Recently, efforts in characterizing mBC revealed distinctive genomic, epigenomic and transcriptomic (multi-omic) landscapes to that of the primary tumor. Understanding of the molecular underpinnings of mBC is key to understanding resistance to therapy and the development of novel treatment options. This review summarizes the differential molecular landscapes of BC and mBC, provides insights into the genomic heterogeneity of mBC and highlights the therapeutically relevant, multi-omic features that may serve as novel therapeutic targets for mBC patients.
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Affiliation(s)
- Guang Yang
- School of Sciences, China Pharmaceutical University, Nanjing 211121, China
- China Grand Enterprises, Beijing 100101, China
| | - Tao Lu
- School of Sciences, China Pharmaceutical University, Nanjing 211121, China
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211121, China
| | - Daniel J. Weisenberger
- Department of Biochemistry and Molecular Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
| | - Gangning Liang
- Department of Urology, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
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Ribeiro R, Carvalho MJ, Goncalves J, Moreira JN. Immunotherapy in triple-negative breast cancer: Insights into tumor immune landscape and therapeutic opportunities. Front Mol Biosci 2022; 9:903065. [PMID: 36060249 PMCID: PMC9437219 DOI: 10.3389/fmolb.2022.903065] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 07/13/2022] [Indexed: 12/24/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer that represents 15-20% of breast tumors and is more prevalent in young pre-menopausal women. It is the subtype of breast cancers with the highest metastatic potential and recurrence at the first 5 years after diagnosis. In addition, mortality increases when a complete pathological response is not achieved. As TNBC cells lack estrogen, progesterone, and HER2 receptors, patients do not respond well to hormone and anti-HER2 therapies, and conventional chemotherapy remains the standard treatment. Despite efforts to develop targeted therapies, this disease continues to have a high unmet medical need, and there is an urgent demand for customized diagnosis and therapeutics. As immunotherapy is changing the paradigm of anticancer treatment, it arises as an alternative treatment for TNBC patients. TNBC is classified as an immunogenic subtype of breast cancer due to its high levels of tumor mutational burden and presence of immune cell infiltrates. This review addresses the implications of these characteristics for the diagnosis, treatment, and prognosis of the disease. Herein, the role of immune gene signatures and tumor-infiltrating lymphocytes as biomarkers in TNBC is reviewed, identifying their application in patient diagnosis and stratification, as well as predictors of efficacy. The expression of PD-L1 expression is already considered to be predictive of response to checkpoint inhibitor therapy, but the challenges regarding its value as biomarker are described. Moreover, the rationales for different formats of immunotherapy against TNBC currently under clinical research are discussed, and major clinical trials are highlighted. Immune checkpoint inhibitors have demonstrated clinical benefit, particularly in early-stage tumors and when administered in combination with chemotherapy, with several regimens approved by the regulatory authorities. The success of antibody-drug conjugates and research on other emerging approaches, such as vaccines and cell therapies, will also be addressed. These advances give hope on the development of personalized, more effective, and safe treatments, which will improve the survival and quality of life of patients with TNBC.
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Affiliation(s)
- Rita Ribeiro
- CNC—Center for Neurosciences and Cell Biology, Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Faculty of Medicine (Polo 1), Coimbra, Portugal
- iMed.ULisboa—Research Institute for Medicines, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal
- Univ Coimbra—University of Coimbra, CIBB, Faculty of Pharmacy, Coimbra, Portugal
| | - Maria João Carvalho
- Univ Coimbra—University of Coimbra, CIBB, Faculty of Pharmacy, Coimbra, Portugal
- CHUC—Coimbra Hospital and University Centre, Department of Gynaecology, Coimbra, Portugal
- Univ Coimbra—University Clinic of Gynaecology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- iCBR—Institute for Clinical and Biomedical Research Area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- CACC—Clinical Academic Center of Coimbra, Coimbra, Portugal
| | - João Goncalves
- iMed.ULisboa—Research Institute for Medicines, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal
| | - João Nuno Moreira
- CNC—Center for Neurosciences and Cell Biology, Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Faculty of Medicine (Polo 1), Coimbra, Portugal
- Univ Coimbra—University of Coimbra, CIBB, Faculty of Pharmacy, Coimbra, Portugal
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Gondhowiardjo SA, Adham M, Rachmadi L, Atmakusuma TD, Tobing DL, Auzan M, Hariyanto AD, Sulaeman D, Permata TBM, Handoko. Immune cells markers within local tumor microenvironment are associated with EBV oncoprotein in nasopharyngeal cancer. BMC Cancer 2022; 22:887. [PMID: 35963999 PMCID: PMC9375267 DOI: 10.1186/s12885-022-09948-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 07/29/2022] [Indexed: 11/29/2022] Open
Abstract
Introduction EBV infection in nasopharyngeal cancer ensued in latent infection mode. In this latent infection various EBV oncoproteins such as EBNA1 and LMP1 was expressed. EBV oncoproteins could theoretically recruit immune cells, which might help to control cancer. Therefore, this study was aimed to elucidate the association with EBV oncoproteins (EBNA1 and LMP1), immune markers (CD4, CD8, and FOXP3) from nasopharyngeal cancer microenvironment with tumor progression. Method Nasopharyngeal biopsy was obtained from patients suspected to have nasopharyngeal cancer. Those samples with microscopically confirmed nasopharyngeal cancer were tested for EBNA1, LMP1, CD4, CD8, and FOXP3 concentration with ELISA, then verified with IHC. Each patient tumor volume was assessed for primary nasopharyngeal tumor volume (GTVp) and neck nodal metastases tumor volume (GTVn). Correlation test with Spearman correlation and scatterplot were carried out. Result Total 23 samples with nasopharyngeal cancer were analyzed. There was moderate correlation (ρ = 0.45; p value = 0.032) between LMP1 and GTVp. There was strong correlation (ρ = 0.81; p value < 0.001) between CD8 and GTVp. There was also moderate correlation (ρ = 0.6; p value = 0.002) between FOXP3 and GTVp. The CD8 concentration has moderate correlation with both EBNA1 (ρ = 0.46; p value = 0.026) and LMP1 (ρ = 0.47; p value = 0.023). While FOXP3 has moderate correlation with only LMP1 (ρ = 0.58; p value = 0.004). No correlation was found between all the markers tested here with GTVn. Discussion We found larger primary nasopharyngeal tumor was associated with higher CD8 marker. This was thought due to the presence of abundance CD8 T cells in the nasopharynx, but those abundance CD8 T cells were suspected to be dysfunctional. The nasopharyngeal cancer was also known to upregulate chemokines that could recruit T regulatory FOXP3 cells. Furthermore, T regulatory FOXP3 cells differentiation was induced through several pathways which was triggered by EBNA1. The correlation found in this study could guide further study to understand nasopharyngeal carcinogenesis and the relationship with our immune system.
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Affiliation(s)
- Soehartati A Gondhowiardjo
- Department of Radiation Oncology, Faculty of Medicine, Universitas Indonesia / Cipto Mangunkusumo National General Hospital, Jakarta - Indonesia, Jl. Salemba Raya No. 6, Jakarta, Indonesia, 10430
| | - Marlinda Adham
- Department of ENT, Faculty of Medicine, Universitas Indonesia / Cipto Mangunkusumo National General Hospital, Jakarta - Indonesia, Jl. Salemba Raya No. 6, Jakarta, Indonesia, 10430
| | - Lisnawati Rachmadi
- Department of Anatomical Pathology, Faculty of Medicine, Universitas Indonesia / Cipto Mangunkusumo National General Hospital, Jakarta - Indonesia, Jl. Salemba Raya No. 6, Jakarta, Indonesia, 10430
| | - Tubagus Djumhana Atmakusuma
- Department of Medical Oncology, Faculty of Medicine, Universitas Indonesia / Cipto Mangunkusumo National General Hospital, Jakarta - Indonesia, Jl. Salemba Raya No. 6, Jakarta, Indonesia, 10430
| | - Demak Lumban Tobing
- Department of Clinical Pathology, Dharmais National Cancer Hospital, Jakarta - Indonesia, Jl. Letjen S. Parman No. 84-86, Jakarta, Indonesia, 11420
| | - Mahesa Auzan
- Department of Radiation Oncology, Faculty of Medicine, Universitas Indonesia / Cipto Mangunkusumo National General Hospital, Jakarta - Indonesia, Jl. Salemba Raya No. 6, Jakarta, Indonesia, 10430
| | - Agustinus Darmadi Hariyanto
- Department of Radiation Oncology, Faculty of Medicine, Universitas Indonesia / Cipto Mangunkusumo National General Hospital, Jakarta - Indonesia, Jl. Salemba Raya No. 6, Jakarta, Indonesia, 10430
| | - Dede Sulaeman
- Department of Radiation Oncology, Faculty of Medicine, Universitas Indonesia / Cipto Mangunkusumo National General Hospital, Jakarta - Indonesia, Jl. Salemba Raya No. 6, Jakarta, Indonesia, 10430
| | - Tiara Bunga Mayang Permata
- Department of Radiation Oncology, Faculty of Medicine, Universitas Indonesia / Cipto Mangunkusumo National General Hospital, Jakarta - Indonesia, Jl. Salemba Raya No. 6, Jakarta, Indonesia, 10430
| | - Handoko
- Department of Radiation Oncology, Faculty of Medicine, Universitas Indonesia / Cipto Mangunkusumo National General Hospital, Jakarta - Indonesia, Jl. Salemba Raya No. 6, Jakarta, Indonesia, 10430.
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Qiang Z, Dai K, He Y, Yang Z, Tao L, Zhang H, Yu H. The prognostic value of stromal tumor-infiltrating lymphocytes in intrahepatic cholangiocarcinoma: a population-based study. Scand J Gastroenterol 2022; 57:965-971. [PMID: 35522155 DOI: 10.1080/00365521.2022.2055972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE We assess the predictive value impacted by tumor-infiltrating lymphocytes (TILs) for overall survival (OS) and progression-free survival (PFS) in patients with intrahepatic cholangiocarcinoma (ICC) undergoing complete resection. METHODS Sixty-eight patients with resectable ICC were included in this study. We studied stromal TIL density and scored it by staining sections from surgically resected ICC patients with hematoxylin and eosin (HE). The clinical data and prognosis of patients with ICC were obtained by searching clinical and follow-up records. RESULTS A stromal TIL negative status was a predictor of poor OS (HR = 0.41, 95% CI 0.20-0.83, p = .01) and poor PFS (HR = 0.47, 95% CI 0.23-0.97, p = .04) independently. Low stromal TIL density was associated with high levels of CA125 (p = .03) and CA19-9 (p < .01). The high level of CA19-9 (p = .05), high differentiation (p = .02), a large diameter (p = .05), a positive bile duct/vascular cancer embolus (p = .03) and positive satellite nodules (p = .02) were tendencies to develop tumors for patients with a negative status of stromal TIL. CONCLUSION Our data prompt for the prediction of the PFS and OS of patients with ICC after complete resection, stromal TILs play an important role.
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Affiliation(s)
- Zeyuan Qiang
- Department of Hepatobiliary Surgery, Henan University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, China
| | - Kunfu Dai
- Department of Hepatobiliary Surgery, Henan University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, China
| | - Yuting He
- Department of Hepatobiliary Surgery, People's Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenwei Yang
- Department of Hepatobiliary Surgery, Henan University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, China
| | - Lianyuan Tao
- Department of Hepatobiliary Surgery, Henan University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, China
| | - Huifeng Zhang
- Department of Hepatobiliary Surgery, Henan University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, China.,Department of Critical Care Medicine, Henan Provincial People's Hospital, Zhengzhou, China
| | - Haibo Yu
- Department of Hepatobiliary Surgery, Henan University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, China.,Department of Hepatobiliary Surgery, People's Hospital of Zhengzhou University, Zhengzhou, China
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Milovanović J, Todorović-Raković N, Vujasinović T, Greenman J, Mandušić V, Radulovic M. Can granulysin provide prognostic value in primary breast cancer? Pathol Res Pract 2022; 237:154039. [PMID: 35905663 DOI: 10.1016/j.prp.2022.154039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 07/20/2022] [Indexed: 10/17/2022]
Abstract
BACKGROUND Granulysin (GNLY) is a cytolytic and proinflammatory molecule which also acts as an immune alarmin. The multifunctional nature of this molecule has made it challenging to define its full potential as a biomarker in breast cancer. AIM To evaluate the prognostic value of intratumoral GNLY in primary breast cancer patients and its association with established clinicopathological parameters. PATIENTS AND METHODS The study included 69 node-negative breast cancer patients with known clinicopathological parameters, all of whom had not received any prior hormonal or chemotherapeutic systemic therapy that would interfere with the course of disease. The median follow-up period was 144 months. Steroid hormone receptor status was determined by ligand-binding assay and HER2 status by chromogenic in situ hybridisation (CISH). Intratumoral GNLY mRNA levels were determined by RT-qPCR. Prognostic performance was evaluated by the receiver operating characteristic (ROC), Cox proportional hazards regression and Kaplan-Meier analysis. Classification of patients into GNLYlow and GNLYhigh subgroups was performed by the use of the outcome-oriented cut-off point categorisation approach. RESULTS There was a significant difference between GNLY values of patients without any recurrences and those with local or distant recurrences (Mann-Whitney test, p = 0.05 and p = 0.02, respectively). None of the tested parameters showed prognostic significance for local and distant recurrences when combined. When distant metastases and local recurrences were separated as events, the best prognostic performance was observed for GNLY as compared with any clinicopathological parameter (AUC=0.24 and p = 0.04 for local events; AUC=0.71 and p = 0.03 for distant events). Local recurrence incidence was 0% for the GNLYhigh subgroup and 19% for the GNLYlow subgroup; however distant recurrence incidence was 24% for the GNLYhigh subgroup but only 3% for the GNLYlow subgroup (Kaplan-Meier analysis). A significant positive correlation was found between intratumoral ER and GNLY levels, and a significant negative correlation between tumour grade and GNLY levels. CONCLUSION High levels of granulysin prognosticate low risk of local recurrence but a high risk of distant metastasis in primary, untreated, breast cancer patients.
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Affiliation(s)
- Jelena Milovanović
- Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia.
| | - Nataša Todorović-Raković
- Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia
| | - Tijana Vujasinović
- Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia
| | - John Greenman
- Department of Biomedical Sciences, University of Hull, Hull, UK
| | - Vesna Mandušić
- Department for Radiobiology and Molecular Genetics, Institute of Nuclear Sciences Vinča - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Marko Radulovic
- Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia
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Vesely C, Wong YNS, Childs A, Akarca AU, Dhami P, Vaikkinen H, Conde L, Herrero J, Ogunbiyi O, Gander A, Luong TV, Thirlwell C, Caplin M, Toumpanakis C, Peggs K, Quezada SA, Marafioti T, Meyer T. Systematic Evaluation of the Immune Environment of Small Intestinal Neuroendocrine Tumors. Clin Cancer Res 2022; 28:2657-2668. [PMID: 35320356 PMCID: PMC9359734 DOI: 10.1158/1078-0432.ccr-21-4203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 02/01/2022] [Accepted: 03/21/2022] [Indexed: 01/07/2023]
Abstract
PURPOSE The immune tumor microenvironment and the potential therapeutic opportunities for immunotherapy in small intestinal neuroendocrine tumors (siNET) have not been fully defined. EXPERIMENTAL DESIGN Herein, we studied 40 patients with primary and synchronous metastatic siNETs, and matched blood and normal tissue obtained during surgery. We interrogated the immune checkpoint landscape using multi-parametric flow cytometry. In addition, matched FFPE tissue was obtained for multi-parametric IHC to determine the relative abundance and distribution of T-cell infiltrate. Tumor mutational burden (TMB) was also assessed and correlated with immune infiltration. RESULTS Effector tumor-infiltrating lymphocytes (TIL) had a higher expression of PD-1 in the tumor microenvironment compared with the periphery. In addition, CD8+ TILs had a significantly higher co-expression of PD-1/ICOS and PD-1/CTLA-4 (cytotoxic T lymphocyte antigen-4) and higher levels of PD-1 expression compared with normal tissue. IHC revealed that the majority of cases have ≤10% intra-tumoral T cells but a higher number of peri-tumoral T cells, demonstrating an "exclusion" phenotype. Finally, we confirmed that siNETs have a low TMB compared with other tumor types in the TCGA database but did not find a correlation between TMB and CD8/Treg ratio. CONCLUSIONS Taken together, these results suggest that a combination therapy approach will be required to enhance the immune response, using PD-1 as a checkpoint immunomodulator backbone in combination with other checkpoint targeting molecules (CTLA-4 or ICOS), or with drugs targeting other pathways to recruit "excluded" T cells into the tumor microenvironment to treat patients with siNETs.
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Affiliation(s)
- Clare Vesely
- UCL Cancer Institute, UCL, London, United Kingdom
| | - Yien Ning Sophia Wong
- UCL Cancer Institute, UCL, London, United Kingdom.,Cancer Immunology Unit, Research Department of Hematology, UCL Cancer Institute, UCL, London, United Kingdom
| | - Alexa Childs
- UCL Cancer Institute, UCL, London, United Kingdom.,Royal Free Hospital, Pond Street, London, United Kingdom
| | | | - Pawan Dhami
- UCL Cancer Institute, UCL, London, United Kingdom
| | | | - Lucia Conde
- UCL Cancer Institute, UCL, London, United Kingdom
| | | | | | - Amir Gander
- Royal Free Hospital, Pond Street, London, United Kingdom
| | - Tu Vinh Luong
- Royal Free Hospital, Pond Street, London, United Kingdom
| | - Chrissie Thirlwell
- UCL Cancer Institute, UCL, London, United Kingdom.,The University of Exeter Medical School, Exeter, United Kingdom
| | - Martyn Caplin
- Royal Free Hospital, Pond Street, London, United Kingdom
| | | | - Karl Peggs
- UCL Cancer Institute, UCL, London, United Kingdom.,Cancer Immunology Unit, Research Department of Hematology, UCL Cancer Institute, UCL, London, United Kingdom
| | - Sergio A. Quezada
- UCL Cancer Institute, UCL, London, United Kingdom.,Cancer Immunology Unit, Research Department of Hematology, UCL Cancer Institute, UCL, London, United Kingdom
| | | | - Tim Meyer
- UCL Cancer Institute, UCL, London, United Kingdom.,Royal Free Hospital, Pond Street, London, United Kingdom.,Corresponding Author: Tim Meyer, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD. Phone: 44-207-679-6731; E-mail;
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Regulatory T cells induce a suppressive immune milieu and promote lymph node metastasis in intrahepatic cholangiocarcinoma. Br J Cancer 2022; 127:757-765. [PMID: 35597869 PMCID: PMC9381563 DOI: 10.1038/s41416-022-01838-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 04/24/2022] [Accepted: 04/27/2022] [Indexed: 12/04/2022] Open
Abstract
Background Emerging evidence indicates that immunogenicity plays an important role in intrahepatic cholangiocarcinoma (ICC). Herein, we systematically evaluated the clinical relevance of immunogenicity in ICC. Methods Highly immunogenic ICCs identified in the public dataset and the Cancer Immunome Atlas (TCIA) were assessed to determine the prognostic impact of immunogenicity in ICC and key components after curative resection. We also investigated the clinical relevance of the immune milieu in ICC. Results Using the Gene Expression Omnibus dataset 89749 and TCIA, we identified CD8+/forkhead box P3 (FoxP3)+ tumour-infiltrating lymphocytes (TILs), T-cell immunoglobulin and mucin domain 3 (TIM-3) and human leukocyte antigen-A (HLA-A) in highly immunogenic ICCs. Immunohistochemical analysis of the in-house cohort showed that intratumoral FoxP3+ TILs correlated with CD8+ TILs (P = 0.045, Fisher’s exact test) and that high FoxP3+/CD8+ ratio (FCR) was an important marker for poor survival (P < 0.001, log-rank test). Furthermore, the FCR was higher in tumour-free lymph nodes in ICCs with lymph node metastases than in those without lymph node metastases (P = 0.003, Mann–Whitney U test). Conclusions FCR should be considered an important biomarker that represents the immune environment of ICC based on its potentially important role in tumour progression, especially lymph node metastasis.
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Development of Training Materials for Pathologists to Provide Machine Learning Validation Data of Tumor-Infiltrating Lymphocytes in Breast Cancer. Cancers (Basel) 2022; 14:cancers14102467. [PMID: 35626070 PMCID: PMC9139395 DOI: 10.3390/cancers14102467] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/07/2022] [Accepted: 05/08/2022] [Indexed: 02/05/2023] Open
Abstract
Simple Summary The High Throughput Truthing project aims to develop a dataset of stromal tumor-infiltrating lymphocytes (sTILs) density evaluations in hematoxylin and eosin-stained invasive breast cancer specimens fit for a regulatory purpose. After completion of the pilot study, the analysis demonstrated inconsistencies and gaps in the provided training to pathologists. Select regions of interest (ROIs) were reviewed by an expert panel, who provided annotations and commentary on the challenges of the sTILs assessment. We used these annotations to develop a training document and reference standard for new training materials. These materials will train crowd-sourced pathologists to help create an algorithm validation dataset and contribute to sTILs evaluations in clinical practice. Abstract The High Throughput Truthing project aims to develop a dataset for validating artificial intelligence and machine learning models (AI/ML) fit for regulatory purposes. The context of this AI/ML validation dataset is the reporting of stromal tumor-infiltrating lymphocytes (sTILs) density evaluations in hematoxylin and eosin-stained invasive breast cancer biopsy specimens. After completing the pilot study, we found notable variability in the sTILs estimates as well as inconsistencies and gaps in the provided training to pathologists. Using the pilot study data and an expert panel, we created custom training materials to improve pathologist annotation quality for the pivotal study. We categorized regions of interest (ROIs) based on their mean sTILs density and selected ROIs with the highest and lowest sTILs variability. In a series of eight one-hour sessions, the expert panel reviewed each ROI and provided verbal density estimates and comments on features that confounded the sTILs evaluation. We aggregated and shaped the comments to identify pitfalls and instructions to improve our training materials. From these selected ROIs, we created a training set and proficiency test set to improve pathologist training with the goal to improve data collection for the pivotal study. We are not exploring AI/ML performance in this paper. Instead, we are creating materials that will train crowd-sourced pathologists to be the reference standard in a pivotal study to create an AI/ML model validation dataset. The issues discussed here are also important for clinicians to understand about the evaluation of sTILs in clinical practice and can provide insight to developers of AI/ML models.
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Pirlog R, Chiroi P, Rusu I, Jurj AM, Budisan L, Pop-Bica C, Braicu C, Crisan D, Sabourin JC, Berindan-Neagoe I. Cellular and Molecular Profiling of Tumor Microenvironment and Early-Stage Lung Cancer. Int J Mol Sci 2022; 23:5346. [PMID: 35628157 PMCID: PMC9140615 DOI: 10.3390/ijms23105346] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/09/2022] [Accepted: 05/10/2022] [Indexed: 12/12/2022] Open
Abstract
Lung cancers are broadly divided into two categories: non-small-cell lung carcinoma (NSCLC), which accounts for 80-85% of all cancer cases, and small-cell lung carcinoma (SCLC), which covers the remaining 10-15%. Recent advances in cancer biology and genomics research have allowed an in-depth characterization of lung cancers that have revealed new therapy targets (EGFR, ALK, ROS, and KRAS mutations) and have the potential of revealing even more biomarkers for diagnostic, prognostic, and targeted therapies. A new source of biomarkers is represented by non-coding RNAs, especially microRNAs (miRNAs). MiRNAs are short non-coding RNA sequences that have essential regulatory roles in multiple cancers. Therefore, we aim to investigate the tumor microenvironment (TME) and miRNA tumor profile in a subset of 51 early-stage lung cancer samples (T1 and T2) to better understand early tumor and TME organization and molecular dysregulation. We analyzed the immunohistochemistry expression of CD4 and CD8 as markers of the main TME immune populations, E-cadherin to evaluate early-stage epithelial-to-mesenchymal transition (EMT), and p53, the main altered tumor suppressor gene in lung cancer. Starting from these 4 markers, we identified and validated 4 miRNAs that target TP53 and regulate EMT that can be further investigated as potential early-stage lung cancer biomarkers.
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Affiliation(s)
- Radu Pirlog
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania; (R.P.); (P.C.); (A.M.J.); (L.B.); (C.P.-B.); (C.B.)
| | - Paul Chiroi
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania; (R.P.); (P.C.); (A.M.J.); (L.B.); (C.P.-B.); (C.B.)
| | - Ioana Rusu
- Department of Pathology, Regional Institute of Gastroenterology and Hepatology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania;
| | - Ancuta Maria Jurj
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania; (R.P.); (P.C.); (A.M.J.); (L.B.); (C.P.-B.); (C.B.)
| | - Liviuta Budisan
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania; (R.P.); (P.C.); (A.M.J.); (L.B.); (C.P.-B.); (C.B.)
| | - Cecilia Pop-Bica
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania; (R.P.); (P.C.); (A.M.J.); (L.B.); (C.P.-B.); (C.B.)
| | - Cornelia Braicu
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania; (R.P.); (P.C.); (A.M.J.); (L.B.); (C.P.-B.); (C.B.)
| | - Doinita Crisan
- Department of Morphological Sciences, “Iuliu Hațieganu” University of Medicine and Pharmacy, 6 Pasteur Street, 400349 Cluj-Napoca, Romania
| | - Jean-Christophe Sabourin
- Pathology Department and INSERM U1245, Rouen University Hospital, Normandy University, 76000 Rouen, France;
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania; (R.P.); (P.C.); (A.M.J.); (L.B.); (C.P.-B.); (C.B.)
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Agostinetto E, Montemurro F, Puglisi F, Criscitiello C, Bianchini G, Del Mastro L, Introna M, Tondini C, Santoro A, Zambelli A. Immunotherapy for HER2-Positive Breast Cancer: Clinical Evidence and Future Perspectives. Cancers (Basel) 2022; 14:2136. [PMID: 35565264 PMCID: PMC9105460 DOI: 10.3390/cancers14092136] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/20/2022] [Accepted: 04/22/2022] [Indexed: 02/06/2023] Open
Abstract
Breast cancer is the most common malignancy among women worldwide, and HER2-positive breast cancer accounts for approximately 15% of all breast cancer diagnoses. The advent of HER2-targeting therapies has dramatically improved the survival of these patients, significantly reducing their risk of recurrence and death. However, as a significant proportion of patients ultimately develop resistance to these therapies, it is extremely important to identify new treatments to further improve their clinical outcomes. Immunotherapy has revolutionized the treatment and history of several cancer types, and it has already been approved as a standard of care for patients with triple-negative breast cancer. Based on a strong preclinical rationale, immunotherapy in HER2-positive breast cancer represents an intriguing field that is currently under clinical investigation. There is a close interplay between HER2-targeting therapies (both approved and under investigation) and the immune system, and several new immunotherapeutic strategies, including immune checkpoint inhibitors, CAR-T cells and therapeutic vaccines, are being studied in this disease. In this narrative review, we discuss the clinical evidence and the future perspectives of immunotherapy for patients with HER2-positive breast cancer.
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Affiliation(s)
- Elisa Agostinetto
- Academic Trials Promoting Team, Institut Jules Bordet, L’Université Libre de Bruxelles (U.L.B), 1070 Brussels, Belgium;
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy;
- IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Via Manzoni 56, Rozzano, 20089 Milan, Italy
| | - Filippo Montemurro
- Direzione Breast Unit, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Italy;
| | - Fabio Puglisi
- Department of Medical Oncology, CRO Aviano, National Cancer Institute, IRCCS, 33081 Aviano, Italy;
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy
| | - Carmen Criscitiello
- Division of Early Drug Development, European Institute of Oncology IRCCS, 20141 Milan, Italy;
- Department of Oncology and Hematology, University of Milan, 20122 Milan, Italy
| | - Giampaolo Bianchini
- Department of Medical Oncology, IRCCS Ospedale San Raffaele, 20132 Milan, Italy;
| | - Lucia Del Mastro
- IRCCS Ospedale Policlinico San Martino, Clinica di Oncologia Medica, 16132 Genova, Italy;
- Dipartimento di Medicina Interna e Specialità Medica, Università di Genova, 16124 Genova, Italy
| | - Martino Introna
- UOS Centro di Terapia Cellulare “G. Lanzani”, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy;
| | - Carlo Tondini
- Medical Oncology Unit, ASST Papa Giovanni XXIII, Piazza OMS 1, 27100 Bergamo, Italy;
| | - Armando Santoro
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy;
- IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Via Manzoni 56, Rozzano, 20089 Milan, Italy
| | - Alberto Zambelli
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy;
- IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Via Manzoni 56, Rozzano, 20089 Milan, Italy
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Carlino F, Diana A, Piccolo A, Ventriglia A, Bruno V, De Santo I, Letizia O, De Vita F, Daniele B, Ciardiello F, Orditura M. Immune-Based Therapy in Triple-Negative Breast Cancer: From Molecular Biology to Clinical Practice. Cancers (Basel) 2022; 14:cancers14092102. [PMID: 35565233 PMCID: PMC9103968 DOI: 10.3390/cancers14092102] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 04/16/2022] [Accepted: 04/19/2022] [Indexed: 12/19/2022] Open
Abstract
Triple-negative breast cancer (TNBC) has been considered for many years an orphan disease in terms of therapeutic options, with conventional chemotherapy (CT) still representing the mainstay of treatment in the majority of patients. Although breast cancer (BC) has been historically considered a "cold tumor", exciting progress in the genomic field leading to the characterization of the molecular portrait and the immune profile of TNBC has opened the door to novel therapeutic strategies, including Immune Checkpoint Inhibitors (ICIs), Poly ADP-Ribose Polymerase (PARP) inhibitors and Antibody Drug Conjugates (ADCs). In particular, compared to standard CT, the immune-based approach has been demonstrated to improve progression-free survival (PFS) and overall survival (OS) in metastatic PD-L1-positive TNBC and the pathological complete response rate in the early setting, regardless of PD-L1 expression. To date, PD-L1 has been widely used as a predictor of the response to ICIs; however, many patients do not benefit from the addition of immunotherapy. Therefore, PD-L1 is not a reliable predictive biomarker of the response, and its accuracy remains controversial due to the lack of a consensus about the assay, the antibody, and the scoring system to adopt, as well as the spatial and temporal heterogeneity of the PD-L1 status. In the precision medicine era, there is an urgent need to identify more sensitive biomarkers in the BC immune oncology field other than just PD-L1 expression. Through the characterization of the tumor microenvironment (TME), the analysis of peripheral blood and the evaluation of immune gene signatures, novel potential biomarkers have been explored, such as the Tumor Mutational Burden (TMB), Microsatellite Instability/Mismatch Repair Deficiency (MSI/dMMR) status, genomic and epigenomic alterations and tumor-infiltrating lymphocytes (TILs). This review aims to summarize the recent knowledge on BC immunograms and on the biomarkers proposed to support ICI-based therapy in TNBC, as well as to provide an overview of the potential strategies to enhance the immune response in order to overcome the mechanisms of resistance.
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Affiliation(s)
- Francesca Carlino
- Department of Precision Medicine, Division of Medical Oncology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy; (A.P.); (A.V.); (V.B.); (F.D.V.); (F.C.); (M.O.)
- Medical Oncology Unit, Ospedale Ave Gratia Plena, San Felice a Cancello, 81027 Caserta, Italy; (I.D.S.); (O.L.)
- Correspondence: ; Tel.: +39-349-5152216
| | - Anna Diana
- Medical Oncology Unit, Ospedale del Mare, 80147 Naples, Italy; (A.D.); (B.D.)
| | - Antonio Piccolo
- Department of Precision Medicine, Division of Medical Oncology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy; (A.P.); (A.V.); (V.B.); (F.D.V.); (F.C.); (M.O.)
| | - Anna Ventriglia
- Department of Precision Medicine, Division of Medical Oncology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy; (A.P.); (A.V.); (V.B.); (F.D.V.); (F.C.); (M.O.)
| | - Vincenzo Bruno
- Department of Precision Medicine, Division of Medical Oncology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy; (A.P.); (A.V.); (V.B.); (F.D.V.); (F.C.); (M.O.)
| | - Irene De Santo
- Medical Oncology Unit, Ospedale Ave Gratia Plena, San Felice a Cancello, 81027 Caserta, Italy; (I.D.S.); (O.L.)
| | - Ortensio Letizia
- Medical Oncology Unit, Ospedale Ave Gratia Plena, San Felice a Cancello, 81027 Caserta, Italy; (I.D.S.); (O.L.)
| | - Ferdinando De Vita
- Department of Precision Medicine, Division of Medical Oncology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy; (A.P.); (A.V.); (V.B.); (F.D.V.); (F.C.); (M.O.)
| | - Bruno Daniele
- Medical Oncology Unit, Ospedale del Mare, 80147 Naples, Italy; (A.D.); (B.D.)
| | - Fortunato Ciardiello
- Department of Precision Medicine, Division of Medical Oncology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy; (A.P.); (A.V.); (V.B.); (F.D.V.); (F.C.); (M.O.)
| | - Michele Orditura
- Department of Precision Medicine, Division of Medical Oncology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy; (A.P.); (A.V.); (V.B.); (F.D.V.); (F.C.); (M.O.)
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Investigating the Prognostic Relevance of Tumor Immune Microenvironment and Immune Gene Assembly in Breast Carcinoma Subtypes. Cancers (Basel) 2022; 14:cancers14081942. [PMID: 35454849 PMCID: PMC9031175 DOI: 10.3390/cancers14081942] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 03/29/2022] [Accepted: 04/06/2022] [Indexed: 02/04/2023] Open
Abstract
We hypothesized that different BC subtypes are characterized by spatially distinct tumor immune microenvironment (TIME) and that immune gene assembly of metastatic (Met) and non-metastatic (Ctrl) BCs vary across subtypes. Peritumoral, stromal and intratumoral TIL was assessed on 309 BC cases. Hot, cold and immune-excluded groups were defined, and the prognostic role of this classification was assessed. CD4+/CD8+ positivity was analyzed in 75 cases in four systematically predefined tumor regions. Immune gene expression of Met and Ctrl HER2-negative BCs was compared by using NanoString nCounter technology. The amount of TIL infiltration varied greatly within all BC subtypes. Two-third of the cases were cold tumors with no significant survival difference compared to hot tumors. A lower CD4+/CD8+ ratio at the stromal internal tumor region was significantly associated with longer distant metastasis-free survival. The differentially expressed immune genes between Met and Ctrl varied across the studied BC subtypes with TNBC showing distinct features from the luminal subtypes. The TIME is characterized by a considerable heterogeneity; however, low level of TILs does not equate to disease progression. The differences in immune gene expression observed between Met and Ctrl breast carcinomas call attention to the important role of altered immune function in BC progression.
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Valencia GA, Rioja P, Morante Z, Ruiz R, Fuentes H, Castaneda CA, Vidaurre T, Neciosup S, Gomez HL. Immunotherapy in triple-negative breast cancer: A literature review and new advances. World J Clin Oncol 2022; 13:219-236. [PMID: 35433291 PMCID: PMC8966508 DOI: 10.5306/wjco.v13.i3.219] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 11/23/2021] [Accepted: 02/19/2022] [Indexed: 02/06/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is a highly complex, heterogeneous disease and historically has limited treatment options. It has a high probability of disease recurrence and rapid disease progression despite adequate systemic treatment. Immunotherapy has emerged as an important alternative in the management of this malignancy, showing an impact on progression-free survival and overall survival in selected populations. In this review we focused on immunotherapy and its current relevance in the management of TNBC, including various scenarios (metastatic and early -neoadjuvant, adjuvant-), new advances in this subtype and the research of potential predictive biomarkers of response to treatment.
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Affiliation(s)
| | - Patricia Rioja
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima 15036, Peru
| | - Zaida Morante
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima 15036, Peru
| | - Rossana Ruiz
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima 15036, Peru
| | - Hugo Fuentes
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima 15036, Peru
| | - Carlos A Castaneda
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima 15036, Peru
| | - Tatiana Vidaurre
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima 15036, Peru
| | - Silvia Neciosup
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima 15036, Peru
| | - Henry L Gomez
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima 15036, Peru
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Corchado-Cobos R, García-Sancha N, Mendiburu-Eliçabe M, Gómez-Vecino A, Jiménez-Navas A, Pérez-Baena MJ, Holgado-Madruga M, Mao JH, Cañueto J, Castillo-Lluva S, Pérez-Losada J. Pathophysiological Integration of Metabolic Reprogramming in Breast Cancer. Cancers (Basel) 2022; 14:cancers14020322. [PMID: 35053485 PMCID: PMC8773662 DOI: 10.3390/cancers14020322] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 01/03/2022] [Accepted: 01/06/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Tumors exhibit metabolic changes that differentiate them from the normal tissues from which they derive. These metabolic changes favor tumor growth, are primarily induced by cancer cells, and produce metabolic and functional changes in the surrounding stromal cells. There is a close functional connection between the metabolic changes in tumor cells and those that appear in the surrounding stroma. A better understanding of intratumoral metabolic interactions may help identify new vulnerabilities that will facilitate new, more individualized treatment strategies against cancer. We review the metabolic changes described in tumor and stromal cells and their functional changes and then consider, in depth, the metabolic interactions between the cells of the two compartments. Although these changes are generic, we illustrate them mainly with reference to examples in breast cancer. Abstract Metabolic changes that facilitate tumor growth are one of the hallmarks of cancer. The triggers of these metabolic changes are located in the tumor parenchymal cells, where oncogenic mutations induce an imperative need to proliferate and cause tumor initiation and progression. Cancer cells undergo significant metabolic reorganization during disease progression that is tailored to their energy demands and fluctuating environmental conditions. Oxidative stress plays an essential role as a trigger under such conditions. These metabolic changes are the consequence of the interaction between tumor cells and stromal myofibroblasts. The metabolic changes in tumor cells include protein anabolism and the synthesis of cell membranes and nucleic acids, which all facilitate cell proliferation. They are linked to catabolism and autophagy in stromal myofibroblasts, causing the release of nutrients for the cells of the tumor parenchyma. Metabolic changes lead to an interstitium deficient in nutrients, such as glucose and amino acids, and acidification by lactic acid. Together with hypoxia, they produce functional changes in other cells of the tumor stroma, such as many immune subpopulations and endothelial cells, which lead to tumor growth. Thus, immune cells favor tissue growth through changes in immunosuppression. This review considers some of the metabolic changes described in breast cancer.
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Affiliation(s)
- Roberto Corchado-Cobos
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain; (R.C.-C.); (N.G.-S.); (M.M.-E.); (A.G.-V.); (A.J.-N.); (M.J.P.-B.); (J.C.)
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain;
| | - Natalia García-Sancha
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain; (R.C.-C.); (N.G.-S.); (M.M.-E.); (A.G.-V.); (A.J.-N.); (M.J.P.-B.); (J.C.)
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain;
| | - Marina Mendiburu-Eliçabe
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain; (R.C.-C.); (N.G.-S.); (M.M.-E.); (A.G.-V.); (A.J.-N.); (M.J.P.-B.); (J.C.)
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain;
| | - Aurora Gómez-Vecino
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain; (R.C.-C.); (N.G.-S.); (M.M.-E.); (A.G.-V.); (A.J.-N.); (M.J.P.-B.); (J.C.)
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain;
| | - Alejandro Jiménez-Navas
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain; (R.C.-C.); (N.G.-S.); (M.M.-E.); (A.G.-V.); (A.J.-N.); (M.J.P.-B.); (J.C.)
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain;
| | - Manuel Jesús Pérez-Baena
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain; (R.C.-C.); (N.G.-S.); (M.M.-E.); (A.G.-V.); (A.J.-N.); (M.J.P.-B.); (J.C.)
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain;
| | - Marina Holgado-Madruga
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain;
- Departamento de Fisiología y Farmacología, Universidad de Salamanca, 37007 Salamanca, Spain
- Instituto de Neurociencias de Castilla y León (INCyL), Universidad de Salamanca, 37007 Salamanca, Spain
| | - Jian-Hua Mao
- Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA;
- Berkeley Biomedical Data Science Center, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Javier Cañueto
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain; (R.C.-C.); (N.G.-S.); (M.M.-E.); (A.G.-V.); (A.J.-N.); (M.J.P.-B.); (J.C.)
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain;
- Departamento de Dermatología, Hospital Universitario de Salamanca, Paseo de San Vicente 58-182, 37007 Salamanca, Spain
- Complejo Asistencial Universitario de Salamanca, 37007 Salamanca, Spain
| | - Sonia Castillo-Lluva
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas, Universidad Complutense, 28040 Madrid, Spain
- Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040 Madrid, Spain
- Correspondence: (S.C.-L.); (J.P-L.)
| | - Jesús Pérez-Losada
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain; (R.C.-C.); (N.G.-S.); (M.M.-E.); (A.G.-V.); (A.J.-N.); (M.J.P.-B.); (J.C.)
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain;
- Correspondence: (S.C.-L.); (J.P-L.)
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Liang S, Willis J, Dou J, Mohanty V, Huang Y, Vilar E, Chen K. Sensei: how many samples to tell a change in cell type abundance? BMC Bioinformatics 2022; 23:2. [PMID: 34983369 PMCID: PMC8728970 DOI: 10.1186/s12859-021-04526-5] [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: 06/19/2021] [Accepted: 12/13/2021] [Indexed: 11/10/2022] Open
Abstract
Cellular heterogeneity underlies cancer evolution and metastasis. Advances in single-cell technologies such as single-cell RNA sequencing and mass cytometry have enabled interrogation of cell type-specific expression profiles and abundance across heterogeneous cancer samples obtained from clinical trials and preclinical studies. However, challenges remain in determining sample sizes needed for ascertaining changes in cell type abundances in a controlled study. To address this statistical challenge, we have developed a new approach, named Sensei, to determine the number of samples and the number of cells that are required to ascertain such changes between two groups of samples in single-cell studies. Sensei expands the t-test and models the cell abundances using a beta-binomial distribution. We evaluate the mathematical accuracy of Sensei and provide practical guidelines on over 20 cell types in over 30 cancer types based on knowledge acquired from the cancer cell atlas (TCGA) and prior single-cell studies. We provide a web application to enable user-friendly study design via https://kchen-lab.github.io/sensei/table_beta.html .
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Affiliation(s)
- Shaoheng Liang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX USA
- Department of Computer Science, Rice University, Houston, TX USA
| | - Jason Willis
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Jinzhuang Dou
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Vakul Mohanty
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Yuefan Huang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Eduardo Vilar
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Ken Chen
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX USA
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Chen L, Chen Y, Zhang L, Xue Y, Zhang S, Li X, Song H. In Gastric Cancer Patients Receiving Neoadjuvant Chemotherapy Systemic Inflammation Response Index is a Useful Prognostic Indicator. Pathol Oncol Res 2021; 27:1609811. [PMID: 34712105 PMCID: PMC8546636 DOI: 10.3389/pore.2021.1609811] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 08/27/2021] [Indexed: 11/30/2022]
Abstract
Background: The preoperative systemic inflammation response index (SIRI), based on peripheral neutrophil (N), monocyte (M), and lymphocyte (L) counts, has shown mounting evidence as an effective prognostic indicator in some malignant tumors. The aim of the present study was to evaluate the prognostic significance of pre-treatment SIRI in gastric cancer patients who received neoadjuvant chemotherapy (NACT). Methods: This retrospective study comprised 107 patients with advanced gastric cancer treated with NACT between July 2007 and September 2015 in our hospital. SIRI was calculated from peripheral venous blood samples obtained prior to treatment. The best cutoff value for SIRI by receiver operating characteristic (ROC) curve was 1.2 (low SIRI <1.21, high SIRI ≥1.21). The clinical outcomes of disease-free survival (DFS) and overall survival (OS) were analyzed by Kaplan-Meier survival analysis and compared using the log-rank test. Univariate and multivariate analyses were performed by the Cox proportional hazards regression model. Results: The results demonstrated that the low SIRI group was statistically associated with gender, primary tumor site, white blood cell, neutrophil, and monocyte counts, NLR (neutrophil to lymphocyte ratio), MLR (monocyte to lymphocyte ratio), and PLR (platelet to lymphocyte ratio). The SIRI was predictive for DFS and OS by univariate and multivariate analysis; the low SIRI group had better median DFS and OS than the high SIRI group (median DFS 27.03 vs. 22.33 months, median OS 29.73 vs. 24.43 months). The DFS and OS in the low SIRI group were longer than the high SIRI group. Conclusions: SIRI may qualify as a useful, reliable, and convenient prognostic indicator in patients with advanced gastric cancer to help physicians to provide personalized prognostication for gastric cancer patients treated with NACT.
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Affiliation(s)
- Li Chen
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China
| | - Yong Chen
- Department of General Surgery, Huai'an Second People's Hospital and the Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, China
| | - Lele Zhang
- Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China
| | - Yingwei Xue
- Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China
| | - Shiwei Zhang
- Department of Oncology Surgery, The First People's Hospital of Fuyang Hangzhou, Hangzhou, China
| | - Xingrui Li
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongjiang Song
- Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China
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Pang J, Wang S, Liao L, Liu X. Association between systemic immune-inflammation index and neoadjuvant chemotherapy efficacy as well as prognosis in triple-negative breast cancer. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2021; 46:958-965. [PMID: 34707005 PMCID: PMC10930184 DOI: 10.11817/j.issn.1672-7347.2021.200951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Indexed: 11/03/2022]
Abstract
OBJECTIVES Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with a relatively poor prognosis. Neoadjuvant chemotherapy (NAC) is the main treatment method. Due to the heterogeneity of the tumor, the chemotherapy response of TNBC patients is significantly different. Inflammation is closely related to the occurrence and development of cancer. The systemic immune-inflammation index (SII) is an indicator that can comprehensively reflect the state of systemic inflammation. This study aims to explore the association between SII and the NAC efficacy as well as the prognosis in TNBC. METHODS The data of TNBC patients who underwent NAC and systemic treatment in Xiangya Hospital of Central South University from January 2015 to June 2019 were collected. According to the inclusion and exclusion criteria, 231 TNBC patients were finally included. The pre-NAC SII was calculated according to the blood routine results of the patients at 1 week before chemotherapy, and the patients were divided into a pre-NAC low SII group (SII<412, 115 cases) and a pre-NAC high SII group (SII≥412, 116 cases). The SII after chemotherapy was calculated according to the blood routine results of the patients at 2 to 3 months after the end of chemotherapy, and the patients were divided into a low SII group after chemotherapy (SII<474, 115 cases) and a high SII group after chemotherapy (SII≥474, 116 cases). Pearson's chi-square test was used to analyze the relationship between SII and other clinical characteristics of TNBC patients, and the relationship between the NAC efficacy and clinical characteristics of TNBC patients. Binary logistic regression analysis was used to find independent factors that affect the efficacy of NAC in TNBC patients. Kaplan-Meier curve analysis was used to analyze factors affecting the prognosis of TNBC patients. Cox regression model was used to find independent factors affecting the prognosis of TNBC patients. RESULTS Before NAC, the differences in SII between groups with different ages and tumor sizes were significant (P=0.007 and P=0.002, respectively); after chemotherapy, there were no significant differences in SII between different ages, tumor sizes, histological grades, lymph node staging, and Ki-67 groups (all P>0.05). There were 115 patients with low SII before NAC, with a pathological complete response (pCR) rate of 15.7%; there were 116 patients with high SII before NAC, with a pCR rate of 6.0%. Patients with low SII before NAC had a higher pCR rate than patients with high SII before NAC, and the difference was statistically significant (P=0.019).There were 156 patients with lymph node staging pN0, with a pCR rate of 14.7%; and there were 75 patients with lymph node staging pN1-pN2, with a pCR rate of 2.7%. Patients with lymph node staging pN0 had a higher pCR rate than those with lymph node staging pN1-pN2, and the difference was significant (P=0.006). During the follow-up, 34 patients had local recurrence or distant metastasis. The Kaplan-Meier survival curve showed that the 3-year disease-free survival (DFS) rates for patients with low SII before NAC and high SII before NAC were 87.8% and 82.8%, respectively, and the former was significantly higher than the latter (P=0.005); the 3-year DFS rates for patients with tumor sizes of T1-T2 and T3 were 89.0% and 67.5%, respectively, and the former was significantly higher than the latter (P=0.001); the 3-year DFS rates for patients with lymph node staging of pN0 and pN1-pN2 were 87.8% and 82.8%, respectively, and the former was significantly higher than the latter (P=0.009). Cox analysis showed that SII before NAC and tumor size were independent influencing factors of patients' DFS (P=0.038, P=0.010, respectively). CONCLUSIONS SII has important clinical significance in predicting the efficacy and prognosis of NAC in TNBC patients, and it has the potential to be a biomarker.
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Affiliation(s)
- Jian Pang
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha 410011.
| | - Shouman Wang
- Department of Breast Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Liqiu Liao
- Department of Breast Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Xiangyan Liu
- Department of Breast Surgery, Xiangya Hospital, Central South University, Changsha 410008, China.
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Jeong S, Lee N, Park MJ, Jeon K, Song W. Currently Used Laboratory Methodologies for Assays Detecting PD-1, PD-L1, PD-L2 and Soluble PD-L1 in Patients with Metastatic Breast Cancer. Cancers (Basel) 2021; 13:cancers13205225. [PMID: 34680373 PMCID: PMC8534186 DOI: 10.3390/cancers13205225] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/07/2021] [Accepted: 10/13/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Several methods targeting the programmed death protein-1 (PD-1) axis have been developed and evaluated for the detection of immune checkpoint levels that are strongly involved in immunotherapy for patients with metastatic breast cancer. Variations in different assays used in diverse studies have affected their result interpretation and clinical utility. When applying these assays to the laboratory, a comprehensive understanding of the characteristics of them should be recognized. We reviewed applied laboratory techniques for detecting PD-1, PD-ligand (L)1, PD-L2, and soluble PD-L1, which are important for selecting metastatic cancer patients for immunotherapy. Advances in methodologies according to the epoch are also investigated to gain insight into immunologic techniques and to facilitate appropriate laboratory settings for evaluating the PD-1 axis status, which are useful for estimating outcomes and planning patient-tailored immunotherapy strategies. Abstract Approximately 20% of breast cancer (BC) patients suffer from distant metastasis. The incidence and prevalence rates of metastatic BC have increased annually. Immune checkpoint inhibitors are an emerging area of treatment, especially for metastatic patients with poor outcomes. Several antibody drugs have been developed and approved for companion testing of the programmed death protine-1 (PD-1) axis. We reviewed currently used laboratory methodologies for assays determining PD-1 axis to provide a comprehensive understanding of principles, advantages, and drawbacks involved in their implementation. The most commonly used method is immunohistochemistry (92.9%) for PD-L1 expression using tissue samples (96.4%). The commonly used anti-PD-L1 antibody clone were commercially available 22C3 (30.8%), SP142 (19.2%), SP263 (15.4%), and E1L3N (11.5%). Enzyme-linked immunosorbent assay and electrochemiluminescent immunoassay that target soluble PD-ligand (L)1 were developed and popularized in 2019–2021, in contrast to 2016–2018. Easy accessibility and non-invasiveness due to the use of blood samples, quantitative outputs, and relatively rapid turnaround times make them more preferable. Regarding scoring methods, a combination of tumor and immune cells (45.5% in 2016–2018 to 57.1% in 2019–2021) rather than each cell alone became more popular. Information about antibody clones, platforms, scoring methods, and related companion drugs is recommended for reporting PD-L1 expression.
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Affiliation(s)
- Seri Jeong
- Department of Laboratory Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07440, Korea; (S.J.); (N.L.); (M.-J.P.)
| | - Nuri Lee
- Department of Laboratory Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07440, Korea; (S.J.); (N.L.); (M.-J.P.)
| | - Min-Jeong Park
- Department of Laboratory Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07440, Korea; (S.J.); (N.L.); (M.-J.P.)
| | - Kibum Jeon
- Department of Laboratory Medicine, Hangang Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07440, Korea;
| | - Wonkeun Song
- Department of Laboratory Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07440, Korea; (S.J.); (N.L.); (M.-J.P.)
- Correspondence: ; Tel.: +82-2-829-5259
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Criscitiello C, Guerini-Rocco E, Viale G, Fumagalli C, Sajjadi E, Venetis K, Piciotti R, Invernizzi M, Malapelle U, Fusco N. Immunotherapy in Breast Cancer Patients: A Focus on the Use of the Currently Available Biomarkers in Oncology. Anticancer Agents Med Chem 2021; 22:787-800. [PMID: 34229592 DOI: 10.2174/1871520621666210706144112] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 01/23/2021] [Accepted: 02/01/2021] [Indexed: 11/22/2022]
Abstract
Immune checkpoint inhibitors (ICIs) have remarkably modified the way solid tumors are managed, including breast cancer. Unfortunately, only a relatively small number of breast cancer patients significantly respond to these treatments. To maximize the immunotherapy benefit in breast cancer, several efforts are currently being put forward for the identification of i) the best therapeutic strategy (i.e. ICI monotherapy or in association with chemotherapy, radiotherapy, or other drugs); ii) the optimal timing for administration (e.g. early/advanced stage of disease; adjuvant/neoadjuvant setting); iii) the most effective and reliable predictive biomarkers of response (e.g. tumor-infiltrating lymphocytes, programmed death-ligand 1, microsatellite instability associated with mismatch repair deficiency, and tumor mutational burden). This article reviews the impacts and gaps in the characterization of immune-related biomarkers raised by clinical and translational research studies with immunotherapy treatments. Particular emphasis has been put on the documented evidence of significant clinical benefits of ICI in different randomized clinical trials, along with preanalytical and analytical issues in predictive biomarkers pathological assessment.
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Affiliation(s)
| | | | - Giulia Viale
- Department of Medical Oncology, IRCCS San Raffaele Hospital, Milan, Italy
| | - Caterina Fumagalli
- Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Elham Sajjadi
- Department of Oncology and Hemato-Oncology, University of Milan, Italy
| | | | - Roberto Piciotti
- Department of Oncology and Hemato-Oncology, University of Milan, Italy
| | - Marco Invernizzi
- Physical and Rehabilitative Medicine, Department of Health Sciences, University of Eastern Piedmont, Viale Piazza D'Armi 1, Novara, Italy
| | - Umberto Malapelle
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Nicola Fusco
- Division of Pathology, IEO, European Institute of Oncology IRCCS, University of Milan, Via Giuseppe Ripamonti 435, 20141, Milan, Italy
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