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de Moraes FCA, Souza MEC, Sano VKT, Moraes RA, Melo AC. Association of tumor-infiltrating lymphocytes with clinical outcomes in patients with triple-negative breast cancer receiving neoadjuvant chemotherapy: a systematic review and meta-analysis. Clin Transl Oncol 2025; 27:974-987. [PMID: 39154313 DOI: 10.1007/s12094-024-03661-8] [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: 06/29/2024] [Accepted: 07/30/2024] [Indexed: 08/19/2024]
Abstract
OBJECTIVE Triple-negative breast cancer (TNBC) presents a clinical challenge as an aggressive tumor, correlated with unfavorable prognosis. Tumor-infiltrating lymphocytes (TILs) have garnered interest as a potential prognostic biomarker. However, the disparity in outcomes between varying TILs rates remains inadequately explored. METHODS PubMed, Scopus, Web of Science, and Cochrane databases were searched for studies about the prognostic value of TILs in patients with TNBC receiving neoadjuvant chemotherapy. The hazard ratios (HRs) or odds ratios (ORs) were computed for binary endpoints, with 95% confidence intervals (CIs). RESULTS Twenty-nine studies were included, involving a population of six thousand one hundred sixty-one (80.41%) with TNBC. The cut-off TILs value ranged from 10 to 60%, with 50% being the most related value. Compared with the low-TIL expression group, the disease-free survival (DFS) (HR 0.71; 95% CI 0.61-0.82; p < 0.00001) and overall survival (OS) (HR 0.76; 95% CI 0.63-0.90; p = 0.002) rates showed significant improvement with higher TIL infiltrations. In the subgroup analyses of the lymphocyte subtypes CD4 + and CD8 + , there was statistical significance favoring higher TILs rates in both subtypes, each associated with improved DFS (HR 0.48; 95% CI 0.33-0.71; p = 0.0002) and OS (HR 0.53; 95% CI 0.36-0.78; p = 0.001), regardless of which cell subtype was predominantly infiltrated. The complete pathological response analysis showed better rates for the higher TIL group than the control for both the TIL (OR 1.29; 95% CI 1.13-1.48; p = 0.0003) and Ki-67 (OR 2.74; 95% CI 2.01-3.73; p < 0.00001) analyses. CONCLUSION Higher expressions of TILs in patients with TNBC were associated with improved significantly DFS, OS, and pCR outcomes.
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Affiliation(s)
| | | | | | | | - Ana C Melo
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX, USA
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Sun HK, Jiang WL, Zhang SL, Xu PC, Wei LM, Liu JB. Predictive value of tumor-infiltrating lymphocytes for neoadjuvant therapy response in triple-negative breast cancer: A systematic review and meta-analysis. World J Clin Oncol 2024; 15:920-935. [PMID: 39071463 PMCID: PMC11271722 DOI: 10.5306/wjco.v15.i7.920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 05/21/2024] [Accepted: 06/06/2024] [Indexed: 07/16/2024] Open
Abstract
BACKGROUND The association between tumor-infiltrating lymphocyte (TIL) levels and the response to neoadjuvant therapy (NAT) in patients with triple-negative breast cancer (TNBC) remains unclear. AIM To investigate the predictive potential of TIL levels for the response to NAT in TNBC patients. METHODS A systematic search of the National Center for Biotechnology Information PubMed database was performed to collect relevant published literature prior to August 31, 2023. The correlation between TIL levels and the NAT pathologic complete response (pCR) in TNBC patients was assessed using a systematic review and meta-analysis. Subgroup analysis, sensitivity analysis, and publication bias analysis were also conducted. RESULTS A total of 32 studies were included in this meta-analysis. The overall meta-analysis results indicated that the pCR rate after NAT treatment in TNBC patients in the high TIL subgroup was significantly greater than that in patients in the low TIL subgroup (48.0% vs 27.7%) (risk ratio 2.01; 95% confidence interval 1.77-2.29; P < 0.001, I 2 = 56%). Subgroup analysis revealed that the between-study heterogeneity originated from differences in study design, TIL level cutoffs, and study populations. Publication bias could have existed in the included studies. The meta-analysis based on different NAT protocols revealed that all TNBC patients with high levels of TILs had a greater rate of pCR after NAT treatment in all protocols (all P ≤ 0.01), and there was no significant between-protocol difference in the statistics among the different NAT protocols (P = 0.29). Additionally, sensitivity analysis demonstrated that the overall results of the meta-analysis remained consistent when the included studies were individually excluded. CONCLUSION TILs can serve as a predictor of the response to NAT treatment in TNBC patients. TNBC patients with high levels of TILs exhibit a greater NAT pCR rate than those with low levels of TILs, and this predictive capability is consistent across different NAT regimens.
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Affiliation(s)
- Hai-Kuan Sun
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan Province, China
| | - Wen-Long Jiang
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan Province, China
| | - Shi-Lei Zhang
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan Province, China
| | - Peng-Cheng Xu
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan Province, China
| | - Li-Min Wei
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan Province, China
| | - Jiang-Bo Liu
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan Province, China
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Hu Y, Lou X, Zhang K, Pan L, Bai Y, Wang L, Wang M, Yan Y, Wan J, Yao X, Duan X, Ni C, Qin Z. Tumor necrosis factor receptor 2 promotes endothelial cell-mediated suppression of CD8+ T cells through tuning glycolysis in chemoresistance of breast cancer. J Transl Med 2024; 22:672. [PMID: 39033271 PMCID: PMC11265105 DOI: 10.1186/s12967-024-05472-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 07/03/2024] [Indexed: 07/23/2024] Open
Abstract
BACKGROUND T cells play a pivotal role in chemotherapy-triggered anti-tumor effects. Emerging evidence underscores the link between impaired anti-tumor immune responses and resistance to paclitaxel therapy in triple-negative breast cancer (TNBC). Tumor-related endothelial cells (ECs) have potential immunoregulatory activity. However, how ECs regulate T cell activity during TNBC chemotherapy remains poorly understood. METHODS Single-cell analysis of ECs in patients with TNBC receiving paclitaxel therapy was performed using an accessible single-cell RNA sequencing (scRNA-seq) dataset to identify key EC subtypes and their immune characteristics. An integrated analysis of a tumor-bearing mouse model, immunofluorescence, and a spatial transcriptome dataset revealed the spatial relationship between ECs, especially Tumor necrosis factor receptor (TNFR) 2+ ECs, and CD8+ T cells. RNA sequencing, CD8+ T cell proliferation assays, flow cytometry, and bioinformatic analyses were performed to explore the immunosuppressive function of TNFR2 in ECs. The downstream metabolic mechanism of TNFR2 was further investigated using RNA sequencing, cellular glycolysis assays, and western blotting. RESULTS In this study, we identified an immunoregulatory EC subtype, characterized by enhanced TNFR2 expression in non-responders. By a mouse model of TNBC, we revealed a dynamic reduction in the proportion of the CD8+ T cell-contacting tumor vessels that could co-localize spatially with CD8+ T cells during chemotherapy and an increased expression of TNFR2 by ECs. TNFR2 suppresses glycolytic activity in ECs by activating NF-κB signaling in vitro. Tuning endothelial glycolysis enhances programmed death-ligand (PD-L) 1-dependent inhibitory capacity, thereby inducing CD8+ T cell suppression. In addition, TNFR2+ ECs showed a greater spatial affinity for exhausted CD8+ T cells than for non-exhausted CD8+ T cells. TNFR2 blockade restores impaired anti-tumor immunity in vivo, leading to the loss of PD-L1 expression by ECs and enhancement of CD8+ T cell infiltration into the tumors. CONCLUSIONS These findings reveal the suppression of CD8+ T cells by ECs in chemoresistance and indicate the critical role of TNFR2 in driving the immunosuppressive capacity of ECs via tuning glycolysis. Targeting endothelial TNFR2 may serve as a potent strategy for treating TNBC with paclitaxel.
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Affiliation(s)
- Yu Hu
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Xiaohan Lou
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Kaili Zhang
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Longze Pan
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
- Department of Medicine, Luohe Medical College, Luohe, 462000, China
| | - Yueyue Bai
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
- Shangqiu Hospital, The First Affiliated Hospital of Henan University of Chinese Medicine, Shangqiu, 476000, China
| | - Linlin Wang
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Ming Wang
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yan Yan
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Jiajia Wan
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Xiaohan Yao
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Xixi Duan
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Chen Ni
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Zhihai Qin
- Henan China-Germany International Joint Laboratory of Tumor Immune Microenvironment and Disease, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
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Xue X, Feng Q, Hong X, Lin Z, Luo Y, Li Y, Yao G, Wang N, Chen L. Comprehensive analysis of ALG3 in pan-cancer and validation of ALG3 as an onco-immunological biomarker in breast cancer. Aging (Albany NY) 2024; 16:2320-2339. [PMID: 38329424 PMCID: PMC10911369 DOI: 10.18632/aging.205483] [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: 09/18/2023] [Accepted: 12/14/2023] [Indexed: 02/09/2024]
Abstract
ALG3 has significant modulatory function in the process of tumor development. Yet how ALG3 involves in the advancement of different malignancies isn't fully understood. We performed a pan-cancer assessment on ALG3 utilizing datasets from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) to examine its tumor-related roles across malignancies and its link to particular molecules and cells in the tumor microenvironment (TME). Furthermore, we focused on breast cancer to examine the influence of ALG3-mediated signaling pathways and intercellular interactions in the advancement of tumors. The biological effects of ALG3 were verified by breast cancer cells. Enhanced ALG3 expression was discovered to be substantially linked to patients' grim prognoses in a number of malignancies. Furthermore, the expression of ALG3 in the TME was linked to the infiltration of stromal and immune cells, and ALG3-related immune checkpoints, TMB, and MSI were also discovered. We also discovered that cancer patients having a high level of ALG3 exhibited a lower probability of benefiting from immunotherapy. Furthermore, our research found that KEGG enrichment, single-cell RNA and spatial sequencing analyses were effective in identifying key signaling pathways in ALG3-associated tumor growth. In vitro, knockdown of ALG3 could decrease the proliferation of breast cancer cells. In summary, our research offers a comprehensive insight into the advancement of tumors under the mediation of ALG3. ALG3 appears to be intimately associated with tumor development in the TME. ALG3 might be a viable treatment target for cancer therapy, particularly in the case of breast cancer.
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Affiliation(s)
- Xiaolei Xue
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Qiaoli Feng
- Breast Center, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Xi Hong
- Breast Center, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Zhousheng Lin
- Breast Center, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Yingrui Luo
- Basic Medical Academy, Cancer Research Institute, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Yingshi Li
- Basic Medical Academy, Cancer Research Institute, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Guangyu Yao
- Breast Center, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Nisha Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Lujia Chen
- Breast Center, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
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Abuhadra N, Sun R, Yam C, Rauch GM, Ding Q, Lim B, Thompson AM, Mittendorf EA, Adrada BE, Damodaran S, Virani K, White J, Ravenberg E, Sun J, Choi J, Candelaria R, Arun B, Ueno NT, Santiago L, Saleem S, Abouharb S, Murthy RK, Ibrahim N, Sahin A, Valero V, Symmans WF, Litton JK, Tripathy D, Moulder S, Huo L. Predictive Roles of Baseline Stromal Tumor-Infiltrating Lymphocytes and Ki-67 in Pathologic Complete Response in an Early-Stage Triple-Negative Breast Cancer Prospective Trial. Cancers (Basel) 2023; 15:3275. [PMID: 37444385 DOI: 10.3390/cancers15133275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 06/11/2023] [Accepted: 06/19/2023] [Indexed: 07/15/2023] Open
Abstract
High stromal tumor-infiltrating lymphocytes (sTILs) are associated with improved pathologic complete response (pCR) in triple-negative breast cancer (TNBC). We hypothesize that integrating high sTILs and additional clinicopathologic features associated with pCR could enhance our ability to predict the group of patients on whom treatment de-escalation strategies could be tested. In this prospective early-stage TNBC neoadjuvant chemotherapy study, pretreatment biopsies from 408 patients were evaluated for their clinical and demographic features, as well as biomarkers including sTILs, Ki-67, PD-L1 and androgen receptor. Multivariate logistic regression models were developed to generate a computed response score to predict pCR. The pCR rate for the entire cohort was 41%. Recursive partitioning analysis identified ≥20% as the optimal cutoff for sTILs to denote 35% (143/408) of patients as having high sTILs, with a pCR rate of 59%, and 65% (265/408) of patients as having low sTILs, with a pCR rate of 31%. High Ki-67 (cutoff > 35%) was identified as the only predictor of pCR in addition to sTILs in the training set. This finding was verified in the testing set, where the highest computed response score encompassing both high sTILa and high Ki-67 predicted a pCR rate of 65%. Integrating Ki67 and sTIL may refine the selection of early stage TNBC patients for neoadjuvant clinical trials evaluating de-escalation strategies.
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Affiliation(s)
- Nour Abuhadra
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ryan Sun
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Clinton Yam
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Gaiane M Rauch
- Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Qingqing Ding
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Bora Lim
- Department of Oncology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Alastair M Thompson
- Division of Surgical Oncology, Section of Breast Surgery, Baylor College of Medicine, Houston, TX 77030, USA
| | - Elizabeth A Mittendorf
- Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Beatriz E Adrada
- Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Senthil Damodaran
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kiran Virani
- Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jason White
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Elizabeth Ravenberg
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jia Sun
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jaihee Choi
- Department of Statistics, Rice University, Houston, TX 77005, USA
| | - Rosalind Candelaria
- Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Banu Arun
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Naoto T Ueno
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Lumarie Santiago
- Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Sadia Saleem
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Sausan Abouharb
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Rashmi K Murthy
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Nuhad Ibrahim
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Aysegul Sahin
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Vicente Valero
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - William Fraser Symmans
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jennifer K Litton
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Debu Tripathy
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Stacy Moulder
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Lei Huo
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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van den Ende NS, Nguyen AH, Jager A, Kok M, Debets R, van Deurzen CHM. Triple-Negative Breast Cancer and Predictive Markers of Response to Neoadjuvant Chemotherapy: A Systematic Review. Int J Mol Sci 2023; 24:ijms24032969. [PMID: 36769287 PMCID: PMC9918290 DOI: 10.3390/ijms24032969] [Citation(s) in RCA: 69] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/27/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Around 40-50% of all triple-negative breast cancer (TNBC) patients achieve a pathological complete response (pCR) after treatment with neoadjuvant chemotherapy (NAC). The identification of biomarkers predicting the response to NAC could be helpful for personalized treatment. This systematic review provides an overview of putative biomarkers at baseline that are predictive for a pCR following NAC. Embase, Medline and Web of Science were searched for articles published between January 2010 and August 2022. The articles had to meet the following criteria: patients with primary invasive TNBC without distant metastases and patients must have received NAC. In total, 2045 articles were screened by two reviewers resulting in the inclusion of 92 articles. Overall, the most frequently reported biomarkers associated with a pCR were a high expression of Ki-67, an expression of PD-L1 and the abundance of tumor-infiltrating lymphocytes, particularly CD8+ T cells, and corresponding immune gene signatures. In addition, our review reveals proteomic, genomic and transcriptomic markers that relate to cancer cells, the tumor microenvironment and the peripheral blood, which also affect chemo-sensitivity. We conclude that a prediction model based on a combination of tumor and immune markers is likely to better stratify TNBC patients with respect to NAC response.
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Affiliation(s)
- Nadine S. van den Ende
- Department of Pathology, Erasmus MC Cancer Institute, Erasmus University Medical Centre, 3015 GD Rotterdam, The Netherlands
- Correspondence: ; Tel.: +31-640213383
| | - Anh H. Nguyen
- Department of Pathology, Erasmus MC Cancer Institute, Erasmus University Medical Centre, 3015 GD Rotterdam, The Netherlands
| | - Agnes Jager
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Centre, 3015 GD Rotterdam, The Netherlands
| | - Marleen Kok
- Department of Medical Oncology, Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
| | - Reno Debets
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Centre, 3015 GD Rotterdam, The Netherlands
| | - Carolien H. M. van Deurzen
- Department of Pathology, Erasmus MC Cancer Institute, Erasmus University Medical Centre, 3015 GD Rotterdam, The Netherlands
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7
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Zhang W, Xu K, Li Z, Wang L, Chen H. Tumor immune microenvironment components and the other markers can predict the efficacy of neoadjuvant chemotherapy for breast cancer. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2023; 25:1579-1593. [PMID: 36652115 DOI: 10.1007/s12094-023-03075-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Accepted: 01/06/2023] [Indexed: 01/19/2023]
Abstract
Breast cancer is an epithelial malignant tumor that occurs in the terminal ducts of the breast. Neoadjuvant chemotherapy (NACT) is an important part of breast cancer treatment. Its purpose is to use systemic treatment for some locally advanced breast cancer patients, to decrease the tumor size and clinical stage so that non-operable breast cancer patients can have a chance to access surgical treatment, or patients who are not suitable for breast-conserving surgery can get the opportunity of breast-conserving. However, some patients who do not respond to NACT will lead deterioration in their condition. Therefore, prediction of NACT efficacy in breast cancer is vital for precision therapy. The tumor microenvironment (TME) has a crucial role in the carcinogenesis and therapeutic response of breast cancer. In this review, we summarized the immune cells, immune checkpoints, and other biomarkers in the TME that can evaluate the efficacy of NACT in treating breast cancer. We believe that the detection and evaluation of the TME components in breast cancer are helpful to predict the efficacy of NACT, and the prediction methods are in the prospect. In addition, we also summarized other predictive factors of NACT, such as imaging examination, biochemical markers, and multigene/multiprotein profiling.
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Affiliation(s)
- Weiqian Zhang
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People's Republic of China.,Department of Pathology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, People's Republic of China
| | - Ke Xu
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People's Republic of China.,Department of Pathology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, People's Republic of China
| | - Zhengfa Li
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People's Republic of China.,Department of Pathology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, People's Republic of China
| | - Linwei Wang
- Department of Oncology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People's Republic of China
| | - Honglei Chen
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People's Republic of China. .,Department of Pathology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, People's Republic of China.
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Dual Role of p73 in Cancer Microenvironment and DNA Damage Response. Cells 2021; 10:cells10123516. [PMID: 34944027 PMCID: PMC8700694 DOI: 10.3390/cells10123516] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/26/2021] [Accepted: 12/03/2021] [Indexed: 12/12/2022] Open
Abstract
Understanding the mechanisms that regulate cancer progression is pivotal for the development of new therapies. Although p53 is mutated in half of human cancers, its family member p73 is not. At the same time, isoforms of p73 are often overexpressed in cancers and p73 can overtake many p53 functions to kill abnormal cells. According to the latest studies, while p73 represses epithelial–mesenchymal transition and metastasis, it can also promote tumour growth by modulating crosstalk between cancer and immune cells in the tumor microenvironment, M2 macrophage polarisation, Th2 T-cell differentiation, and angiogenesis. Thus, p73 likely plays a dual role as a tumor suppressor by regulating apoptosis in response to genotoxic stress or as an oncoprotein by promoting the immunosuppressive environment and immune cell differentiation.
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9
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Zheng H, Siddharth S, Parida S, Wu X, Sharma D. Tumor Microenvironment: Key Players in Triple Negative Breast Cancer Immunomodulation. Cancers (Basel) 2021; 13:cancers13133357. [PMID: 34283088 PMCID: PMC8269090 DOI: 10.3390/cancers13133357] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 06/29/2021] [Accepted: 07/01/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary The tumor microenvironment (TME) is a complicated network composed of various cells, signaling molecules, and extra cellular matrix. TME plays a crucial role in triple negative breast cancer (TNBC) immunomodulation and tumor progression, paradoxically, acting as an immunosuppressive as well as immunoreactive factor. Research regarding tumor immune microenvironment has contributed to a better understanding of TNBC subtype classification. Shall we treat patients precisely according to specific subtype classification? Moving beyond traditional chemotherapy, multiple clinical trials have recently implied the potential benefits of immunotherapy combined with chemotherapy. In this review, we aimed to elucidate the paradoxical role of TME in TNBC immunomodulation, summarize the subtype classification methods for TNBC, and explore the synergistic mechanism of chemotherapy plus immunotherapy. Our study may provide a new direction for the development of combined treatment strategies for TNBC. Abstract Triple negative breast cancer (TNBC) is a heterogeneous disease and is highly related to immunomodulation. As we know, the most effective approach to treat TNBC so far is still chemotherapy. Chemotherapy can induce immunogenic cell death, release of damage-associated molecular patterns (DAMPs), and tumor microenvironment (TME) remodeling; therefore, it will be interesting to investigate the relationship between chemotherapy-induced TME changes and TNBC immunomodulation. In this review, we focus on the immunosuppressive and immunoreactive role of TME in TNBC immunomodulation and the contribution of TME constituents to TNBC subtype classification. Further, we also discuss the role of chemotherapy-induced TME remodeling in modulating TNBC immune response and tumor progression with emphasis on DAMPs-associated molecules including high mobility group box1 (HMGB1), exosomes, and sphingosine-1-phosphate receptor 1 (S1PR1), which may provide us with new clues to explore effective combined treatment options for TNBC.
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Affiliation(s)
- Hongmei Zheng
- Hubei Provincial Clinical Research Center for Breast Cancer, Department of Breast Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430079, China
- The Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA; (S.S.); (S.P.); (D.S.)
- Correspondence: (H.Z.); (X.W.)
| | - Sumit Siddharth
- The Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA; (S.S.); (S.P.); (D.S.)
| | - Sheetal Parida
- The Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA; (S.S.); (S.P.); (D.S.)
| | - Xinhong Wu
- Hubei Provincial Clinical Research Center for Breast Cancer, Department of Breast Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430079, China
- Correspondence: (H.Z.); (X.W.)
| | - Dipali Sharma
- The Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA; (S.S.); (S.P.); (D.S.)
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Strong CD8+ lymphocyte infiltration in combination with expression of HLA class I is associated with better tumor control in breast cancer patients treated with neoadjuvant chemotherapy. Breast Cancer Res Treat 2019; 175:605-615. [PMID: 30868392 PMCID: PMC6534526 DOI: 10.1007/s10549-019-05195-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 03/05/2019] [Indexed: 12/05/2022]
Abstract
Purpose Tumor-infiltrating lymphocytes (TILs) are associated with pathological complete response (pCR) and survival after neoadjuvant chemotherapy (NAC) in patients with early breast cancer. We investigated the prognostic and predictive role of TILs, macrophages, and HLA class 1 expression after NAC with or without the potentially immune modulating compound zoledronic acid (ZA). Methods Baseline tumor biopsies from 196 patients in the NEOZOTAC trial were analyzed for CD8 (cytotoxic T-cells), FoxP3 (regulatory T-cells), CD68 (macrophages), and HLA class I (HCA2/HC10) expression by immunohistochemistry and subsequently related to pCR and disease-free survival (DFS). Results A strong intratumoral CD8+ infiltration or expression of HLA class 1 by cancer cells was associated with a higher pCR rate (p < 0.05). Clinical benefit of high CD8+ T-cell infiltration was found when cancer cells expressed HLA class 1 (pCR: 21.8% vs. 6.7%, p = 0.04) but not when HLA class 1 expression was lost or downregulated (pCR: 5.9% vs. 0%, p = 0.38). Interaction analyses revealed survival benefit between HLA class 1 expression and strong CD8+ T-cell infiltration, whereas in the absence or downregulation of HLA class 1 expression, high levels of CD8+ T-cells were associated with survival disadvantage (p for interaction 0.01; hazard ratio 0.41, 95% CI 0.15–1.10, p = 0.08 and hazard ratio 7.67, 95% CI 0.88–66.4, p = 0.07, respectively). Baseline immune markers were not related to ZA treatment. Conclusions Strong baseline tumor infiltration with CD8+ T-cells in the presence of tumoral HLA class 1 expression in patients with HER2-negative breast cancer is related to a higher pCR rate and a better DFS after NAC. Electronic supplementary material The online version of this article (10.1007/s10549-019-05195-y) contains supplementary material, which is available to authorized users.
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Zhang WJ, Wang XH, Gao ST, Chen C, Xu XY, Sun Q, Zhou ZH, Wu GZ, Yu Q, Xu G, Yao YZ, Guan WX. Tumor-associated macrophages correlate with phenomenon of epithelial-mesenchymal transition and contribute to poor prognosis in triple-negative breast cancer patients. J Surg Res 2017; 222:93-101. [PMID: 29273380 DOI: 10.1016/j.jss.2017.09.035] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 07/03/2017] [Accepted: 09/28/2017] [Indexed: 12/30/2022]
Abstract
BACKGROUND Tumor-associated macrophages (TAMs) are associated with poor outcomes in multiple solid cancers and play important roles in cancer progression. Epithelial-mesenchymal transition (EMT) may account for metastasis and recurrence. However, the association between TAMs and EMT is not clarified in triple-negative breast cancer (TNBC). The aim of this study was to investigate the effects of TAMs on EMT in TNBC. MATERIAL AND METHODS We studied specimens from 278 patients with TNBC. TAMs marker cluster of differentiation 163 and EMT-related marker E-cadherin were detected by immunohistochemistry in TNBC tissues, and their clinical significance was evaluated from the patients' medical records. RESULTS TNBC patients with polarized cluster of differentiation 163+ TAMs infiltration and low level of E-cadherin had a significantly higher risk of aggressive features, including recurrence, histologic differentiation, and lymph node metastasis. Infiltration of TAMs was also negatively correlated with E-cadherin in TNBC tissues. Multivariate analysis indicated that infiltration of TAMs and low expression of E-cadherin were independent prognostic factors of overall survival and disease-free survival in TNBC patients. CONCLUSIONS High infiltration of TAMs was associated with low expression of E-cadherin and could be used as an unfavorable prognostic factor for patients with TNBC.
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Affiliation(s)
- Wei-Jie Zhang
- Department of General Surgery, Drum Tower Clinical College of Nanjing Medical University, Nanjing, China; Department of General Surgery, Affiliated Drum tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Xiao-Hua Wang
- Department of Medical Oncology, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Shao-Ting Gao
- Department of General Surgery, Affiliated Drum tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Cheng Chen
- Department of Radiotherapy, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Xin-Yun Xu
- Department of Pathology, Affiliated Drum tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Qi Sun
- Department of Pathology, Affiliated Drum tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Zhi-Hua Zhou
- Department of Pathology, 101th Hospital of PLA, Wuxi, China
| | - Guo-Zhong Wu
- Department of General Surgery, 101th Hospital of PLA, Wuxi, China
| | - Qiao Yu
- Department of Breast Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, China.
| | - Guifang Xu
- Department of Gastroenterology, Affiliated Drum tower Hospital of Nanjing University Medical School, Nanjing, China.
| | - Yong-Zhong Yao
- Department of General Surgery, Affiliated Drum tower Hospital of Nanjing University Medical School, Nanjing, China.
| | - Wen-Xian Guan
- Department of General Surgery, Drum Tower Clinical College of Nanjing Medical University, Nanjing, China; Department of General Surgery, Affiliated Drum tower Hospital of Nanjing University Medical School, Nanjing, China.
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Kalinski P, Talmadge JE. Tumor Immuno-Environment in Cancer Progression and Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1036:1-18. [PMID: 29275461 DOI: 10.1007/978-3-319-67577-0_1] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The approvals of Provenge (Sipuleucel-T), Ipilimumab (Yervoy/anti-CTLA-4) and blockers of the PD-1 - PD-L1/PD-L2 pathway, such as nivolumab (Opdivo), pembrolizumab (Keytruda), or atezolizumab (Tecentriq), have established immunotherapy as a key component of comprehensive cancer care. Further, murine mechanistic studies and studies in immunocompromised patients have documented the critical role of immunity in effectiveness of radio- and chemotherapy. However, in addition to the ability of the immune system to control cancer progression, it can also promote tumor growth, via regulatory T cells (Tregs), myeloid-derived dendritic cells (MDSCs) and tumor associated macrophages (TAM), which can enhance survival of cancer cells directly or via the regulation of the tumor stroma.An increasing body of evidence supports a central role for the tumor microenvironment (TME) and the interactions between tumor stroma, infiltrating immune cells and cancer cells during the induction and effector phase of anti-cancer immunity, and the overall effectiveness of immunotherapy and other forms of cancer treatment. In this chapter, we discuss the roles of key TME components during tumor progression, metastatic process and cancer therapy-induced tumor regression, as well as opportunities for their modulation to enhance the overall therapeutic benefit.
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Affiliation(s)
- Pawel Kalinski
- Department of Medicine and Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY, USA.
| | - James E Talmadge
- University of Nebraska Medical Center, 986495 Nebraska Medical Center, Omaha, NE, USA
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