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Prognostic impact of a tumor-infiltrating lymphocyte subtype in triple negative cancer of the breast.

ABSTRACT: BACKGROUND:Tumor-infiltrating lymphocytes (TILs) have recently been reported as an important factor in the tumor microenvironment and influence the growth and progression of cancer. However, the relationship between immune cell subpopulations, such as CD4+, CD8+, and FOXP3+, in breast cancer, especially in triple negative carcinoma (TNC), remains unclear. METHODS:The subjects were 107 patients with TNC that were surgically resected at Dokkyo Medical University Hospital between 2006 and 2018. The expression of CD4+, CD8+, and FOXP3+ was evaluated in TILs and expressed as the numbers of positive cells. RESULTS:Univariate analysis revealed that the TILs were not prognostically significant. In multivariate analyses, increased infiltration of intratumoral (i) CD4+?TILs was found to have a good prognosis in relapse-free survival (RFS). In contrast, a high stromal CD8+?TILs level was found to be a favorable prognostic factor in RFS (p?=?0.038) and overall survival (OS) (p?=?0.046). A low sFOXP3?+?TILs level was significantly associated with favorable RFS (p?

SUBMITTER: Jamiyan T

PROVIDER: S-EPMC7438376 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Prognostic impact of a tumor-infiltrating lymphocyte subtype in triple negative cancer of the breast.

Jamiyan Tsengelmaa T Kuroda Hajime H Yamaguchi Rin R Nakazato Yoshimasa Y Noda Shuhei S Onozaki Masato M Abe Akihito A Hayashi Mitsuhiro M

Breast cancer (Tokyo, Japan) 20200328 5

<h4>Background</h4>Tumor-infiltrating lymphocytes (TILs) have recently been reported as an important factor in the tumor microenvironment and influence the growth and progression of cancer. However, the relationship between immune cell subpopulations, such as CD4+, CD8+, and FOXP3+, in breast cancer, especially in triple negative carcinoma (TNC), remains unclear.<h4>Methods</h4>The subjects were 107 patients with TNC that were surgically resected at Dokkyo Medical University Hospital between 200 ...[more]

PMID: 32222891

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Project description:In breast cancer, humoral immune responses may contribute to clinical outcomes, especially in more immunogenic subtypes. Here, we investigated B lymphocyte subsets, immunoglobulin expression, and clonal features in breast tumors, focusing on aggressive triple-negative breast cancers (TNBC). In samples from patients with TNBC and healthy volunteers, circulating and tumor-infiltrating B lymphocytes (TIL-B) were evaluated. CD20+CD27+IgD- isotype-switched B lymphocytes were increased in tumors, compared with matched blood. TIL-B frequently formed stromal clusters with T lymphocytes and engaged in bidirectional functional cross-talk, consistent with gene signatures associated with lymphoid assembly, costimulation, cytokine-cytokine receptor interactions, cytotoxic T-cell activation, and T-cell-dependent B-cell activation. TIL-B-upregulated B-cell receptor (BCR) pathway molecules FOS and JUN, germinal center chemokine regulator RGS1, activation marker CD69, and TNFα signal transduction via NFκB, suggesting BCR-immune complex formation. Expression of genes associated with B lymphocyte recruitment and lymphoid assembly, including CXCL13, CXCR4, and DC-LAMP, was elevated in TNBC compared with other subtypes and normal breast. TIL-B-rich tumors showed expansion of IgG but not IgA isotypes, and IgG isotype switching positively associated with survival outcomes in TNBC. Clonal expansion was biased toward IgG, showing expansive clonal families with specific variable region gene combinations and narrow repertoires. Stronger positive selection pressure was present in the complementarity determining regions of IgG compared with their clonally related IgA in tumor samples. Overall, class-switched B lymphocyte lineage traits were conspicuous in TNBC, associated with improved clinical outcomes, and conferred IgG-biased, clonally expanded, and likely antigen-driven humoral responses. SIGNIFICANCE: Tumor-infiltrating B lymphocytes assemble in clusters, undergoing B-cell receptor-driven activation, proliferation, and isotype switching. Clonally expanded, IgG isotype-biased humoral immunity associates with favorable prognosis primarily in triple-negative breast cancers.

Project description:BackgroundTriple negative breast cancer affects 10% to 20% of all women diagnosed with breast cancer. Due to its characteristics, treatment strategies are limited and metastatic recurrences are common in the first 5 years after treatment. However, not all patients affected by this disease develop metastases. Tumor-infiltrating lymphocytes have shown to be reliable predictive biomarkers of treatment response and metastatic recurrences. However, we need to develop simpler and faster ways to predict response to cytotoxic treatment and the possibility of eventual cancer relapse by identifying new biomarkers. Recently, new studies are emerging, suggesting a predictive role of circulating blood cells in different types of cancer. In this study, we will assess the correlation between tumor-infiltrating lymphocytes and different elements of the blood count in patients diagnosed with triple negative breast cancer.MethodsThe main objective of this study is to evaluate the correlation between the peripheral neutrophil-to-lymphocyte ratio and the amount of tumor-infiltrating lymphocytes, assessed in triple negative breast cancer patients at diagnosis. Secondary objectives include evaluation of the correlation between tumor-infiltrating lymphocytes at diagnosis and the baseline absolute neutrophil, lymphocyte, and platelet counts, as well as the platelet-to-lymphocyte ratio. The triple negative breast cancer patients will be enrolled in the PERCEPTION trial during the first year after the treatment completion. Two supplementary blood tests, at 12 months after the end of treatment and at the time of the first metastatic recurrence, will be performed.DiscussionThe discovery of new prognostic and predictive biomarkers is crucial for triple negative breast cancer. We set up the PERCEPTION clinical trial in order to evaluate certain blood counts as early biomarkers and to assess their correlation with tumor-infiltrating lymphocytes. Demonstration of comparative predictive and/or prognostic capacities of peripheral blood counts and tumor-infiltrating lymphocytes would allow introduction of the former as simple and cheap biomarkers in triple negative breast cancer patient management.Trial registrationThe PERCEPTION study has been registered in the French National Agency of Medical Security registry on the 2nd of July 2019 under the number 2019-A01861-56 and in the ClinicalTrials.org registry under the number NCT04068623.

Dataset Information

Prognostic impact of a tumor-infiltrating lymphocyte subtype in triple negative cancer of the breast.

Publications

Prognostic impact of a tumor-infiltrating lymphocyte subtype in triple negative cancer of the breast.

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