Chemotherapy Shifts the Balance in Favor of CD8+ TNFR2+ TILs in Triple-Negative Breast Tumors

Triple-negative breast cancer (TNBC) is primarily treated via chemotherapy; in parallel, efforts are made to introduce immunotherapies into TNBC treatment. CD4+ TNFR2+ lymphocytes were reported as Tregs that contribute to tumor progression. However, our published study indicated that TNFR2+ tumor-infiltrating lymphocytes (TNFR2+ TILs) were associated with improved survival in TNBC patient tumors. Based on our analyses of the contents of CD4+ and CD8+ TILs in TNBC patient tumors, in the current study, we determined the impact of chemotherapy on CD4+ and CD8+ TIL subsets in TNBC mouse tumors. We found that chemotherapy led to (1) a reduction in CD4+ TNFR2+ FOXP3+ TILs, indicating that chemotherapy decreased the content of CD4+ TNFR2+ Tregs, and (2) an elevation in CD8+ TNFR2+ and CD8+ TNFR2+ PD-1+ TILs; high levels of these two subsets were significantly associated with reduced tumor growth. In spleens of tumor-bearing mice, chemotherapy down-regulated CD4+ TNFR2+ FOXP3+ cells but the subset of CD8+ TNFR2+ PD-1+ was not present prior to chemotherapy and was not increased by the treatment. Thus, our data suggest that chemotherapy promotes the proportion of protective CD8+ TNFR2+ TILs and that, unlike other cancer types, therapeutic strategies directed against TNFR2 may be detrimental in TNBC.

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Metastatic triple-negative breast cancers at first relapse have fewer tumor-infiltrating lymphocytes than their matched primary breast tumors: a pilot study

Human Pathology ◽

10.1016/j.humpath.2013.03.010 ◽

2013 ◽

Vol 44 (10) ◽

pp. 2055-2063 ◽

Cited By ~ 54

Author(s):

Ashley Cimino-Mathews ◽

Xiaobu Ye ◽

Alan Meeker ◽

Pedram Argani ◽

Leisha A. Emens

Keyword(s):

Pilot Study ◽

Triple Negative ◽

Tumor Infiltrating Lymphocytes ◽

Breast Tumors ◽

Breast Cancers ◽

First Relapse ◽

Infiltrating Lymphocytes

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Abstract PR06: Differences in tumor-infiltrating lymphocytes between racially distinct triple-negative breast tumors

10.1158/1538-7755.disp17-pr06 ◽

2018 ◽

Author(s):

Nikita Wright ◽

Chaeyun Lee ◽

Wei Guanhao ◽

Uma Krishnamurti ◽

Xiaoxian Li ◽

...

Keyword(s):

Triple Negative ◽

Tumor Infiltrating Lymphocytes ◽

Breast Tumors ◽

Infiltrating Lymphocytes

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TUMOR-INFILTRATING LYMPHOCYTES IN TRIPLE NEGATIVE BREAST CANCER: CORRELATIVE ANALYSES OF OWN DATA AND LITERATURE REVIEW

Ukrainian Scientific Medical Youth Journal ◽

10.32345/usmyj.2(110).2019.31-41 ◽

2019 ◽

pp. 31-41

Author(s):

Liubov Zakhartseva ◽

Mariia Yanovytska

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Survival Rates ◽

Tumor Infiltrating Lymphocytes ◽

Breast Tumors ◽

Tumor Group ◽

Malignant Breast ◽

Infiltrating Lymphocytes

The article summarizes data and presents own study about the value of tumor-infiltrating lymphocytes as a prognostic factor for breast cancer including triple negative breast cancer lacking estrogen and progesterone receptors and HER2\new amplification. This tumor group is heterogeneous and has lower overall and disease-free survival rates; therapeutic options for this tumor group are limited compared to luminal and HER2-positive tumors. Triple negative breast tumors attract the attention of scientists as they require more individualized approach and additional prognostic factors in the treatment. The aim of this study is to conduct correlation analysis of tumor-infiltrating lymphocytes with survival rates, stage of disease and degree of differentiation of triple negative breast tumors. Also determination of the most "immunogenic" histological subgroups of triple negative breast cancer is done, as well as comparing of tumor-infiltrating lymphocytes measurement as a continuous number and divided into groups. Samples (n = 143) from patients with triple negative breast cancer undergoing treatment at the Kyiv City Clinical Oncology Center during 2010-2015 were used. The assessment of the number of tumor-infiltrating lymphocytes was performed on histological glasses retrospectively, following the recommendations of an international group for the determination of immune-oncological biomarkers. The number of tumor-infiltrating lymphocytes was evaluated as a continuous number and also divided into groups A (0-10%), B (10-40%) and C (40-90%). According to the results of the study, there was a high direct correlation between the continuous number of tumor-infiltrating lymphocytes and divided into groups (A, B, C). A weak direct correlation was found between tumor-infiltrating lymphocytes and tumor differentiation rates, a weak inverse correlation between tumor-infiltrating lymphocytes count and overall survival and stage of disease, in particular tumor size. The rate of tumor-infiltrating lymphocytes for all carcinomas with medullary characteristics was 100%, indicating a high "immunogenicity" of this histological subtype of tumors. The study confirms that tumor-infiltrating lymphocytes act as an additional prognostic marker for malignant breast tumors, in particular, triple negative breast cancer. Determination of tumor-infiltrating lymphocytes is advisable in the routine practice of the pathologist who investigates malignant breast tumors since it requires no additional reactions and is economically viable. It is advisable to use the recommendations of an international group of the determination of immuno-cancer biomarkers for the distribution of this indicator by groups A, B, C for convenience of description.

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Systemic immune reaction in axillary lymph nodes adds to tumor-infiltrating lymphocytes in triple-negative breast cancer prognostication

npj Breast Cancer ◽

10.1038/s41523-021-00292-y ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Fangfang Liu ◽

Thomas Hardiman ◽

Kailiang Wu ◽

Jelmar Quist ◽

Patrycja Gazinska ◽

...

Keyword(s):

Breast Cancer ◽

Immune Responses ◽

Lymph Nodes ◽

Triple Negative ◽

Tumor Infiltrating Lymphocytes ◽

Axillary Lymph Nodes ◽

Axillary Lymph ◽

Her2 Positive ◽

Local Immunity ◽

Infiltrating Lymphocytes

AbstractThe level of stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative (TNBC) and HER2-positive breast cancers convey prognostic information. The importance of systemic immunity to local immunity is unknown in breast cancer. We previously demonstrated that histological alterations in axillary lymph nodes (LNs) carry clinical relevance. Here, we capture local immune responses by scoring TILs at the primary tumor and systemic immune responses by recording the formation of secondary follicles, also known as germinal centers, in 2,857 cancer-free and involved axillary LNs on haematoxylin and eosin (H&E) stained sections from a retrospective cohort of 161 LN-positive triple-negative and HER2-positive breast cancer patients. Our data demonstrate that the number of germinal center formations across all cancer-free LNs, similar to high levels of TILs, is associated with a good prognosis in low TILs TNBC. This highlights the importance of assessing both primary and LN immune responses for prognostication and for future breast cancer research.

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Biomolecular Factors Represented by Bcl-2, p53, and Tumor-Infiltrating Lymphocytes Predict Response for Adjuvant Anthracycline Chemotherapy in Patients with Early Triple-Negative Breast Cancer

Cancer Management and Research ◽

10.2147/cmar.s274104 ◽

2020 ◽

Vol Volume 12 ◽

pp. 11965-11971

Author(s):

Xenia Elena Bacinschi ◽

Anca Zgura ◽

Inga Safta ◽

Rodica Anghel

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Tumor Infiltrating Lymphocytes ◽

Infiltrating Lymphocytes ◽

Anthracycline Chemotherapy

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Tumor microenvironment in triple-negative breast cancer: the correlation of tumor-associated macrophages and tumor-infiltrating lymphocytes

Clinical & Translational Oncology ◽

10.1007/s12094-021-02652-3 ◽

2021 ◽

Author(s):

H. Kuroda ◽

T. Jamiyan ◽

R. Yamaguchi ◽

A. Kakumoto ◽

A. Abe ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Tumor Microenvironment ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cytotoxic T Cells ◽

Tumor Infiltrating Lymphocytes ◽

Tumor Associated Macrophages ◽

Free Survival ◽

Infiltrating Lymphocytes

Abstract Purpose Immune cells such as cytotoxic T cells, helper T cells, B cells or tumor-associated macrophages (TAMs) contribute to the anti-tumor response or pro-tumorigenic effect in triple negative breast cancer (TNBC). The interrelation of TAMs, T and B tumor-infiltrating lymphocytes (TILs) in TNBC has not been fully elucidated. Methods We evaluated the association of tumor-associated macrophages, T and B TILs in TNBC. Results TNBCs with a high CD68+, CD163+ TAMs and low CD4+, CD8+, CD20+ TILs had a significantly shorter relapse-free survival (RFS) and overall survival (OS) than those with low CD68+, CD163+ TAMs and high CD4+, CD8+, CD20+ TILs. TNBCs with high CD68+ TAMs/low CD8+ TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD68+ TAMs/high CD8+ TILs, low CD68+ TAMs/high CD8+ TILs, and low CD68+/low CD8+. TNBCs with high CD163+ TAMs/low CD8+, low CD20 + TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD163+ TAMs/high CD8+ TILs and high CD163+ TAMs /high CD20+ TILs. Conclusions Our study suggests that TAMs further create an optimal tumor microenvironment (TME) for growth and invasion of cancer cells when evasion of immunoreactions due to T and B TILs occurs. In TNBCs, all these events combine to affect prognosis. The process of TME is highly complex in TNBCs and for an improved understanding, larger validation studies are necessary to confirm these findings.

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