Abstract
BackgroundStromal tumor-infiltrating lymphocytes (TILs) are a robust prognostic factor in triple-negative breast cancer (TNBC). However, the clinical significance of TILs may be influenced by the complex landscape of the tumor immune microenvironment. In this study, we aimed to evaluate the composition and the functionality of lymphocytic infiltration and checkpoint receptors in TNBC.MethodsFormalin-fixed, paraffin-embedded tissues were retrospectively collected from a cohort of patients with early-stage TNBC treated with adjuvant anthracycline-based chemotherapy (n = 259). Results were validated in an independent cohort of patients with TNBC (n = 104). Stromal TILs were evaluated on hematoxylin-and-eosin-stained sections. The density of CD4+, CD8+, and FOXP3+ lymphocytes, and the expression of the immune checkpoints PD-1 and LAG-3, were assessed by immunohistochemical analysis.ResultsThe presence of elevated TILs positively correlated with the density of all T cell subtypes, especially cytotoxic CD8+ lymphocytes. We showed that increasing stromal TILs assessed as a continuous variable is an independent prognostic marker of prolonged relapse-free survival and overall survival in TNBC. Among immune subpopulations, CD8+ lymphocytes are the main effectors of anti-tumor immune responses. In two independent cohorts, we found that PD-1 and LAG-3 were concurrently expressed in approximately 15% of patients with TNBC. The expression of both checkpoint receptors positively correlated with the presence of TILs, but was not significantly associated with patient outcome.ConclusionsOverall, our data indicate that the evaluation of stromal TILs remains the most reliable immune prognostic marker in TNBC, and support the clinical evaluation of anti-PD-1/PD-L1 and anti-LAG-3 in a subset of patients with TNBC who have concurrent expression of both checkpoint receptors.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0783-4) contains supplementary material, which is available to authorized users.
Highlights
Stromal tumor-infiltrating lymphocytes (TILs) are a robust prognostic factor in triple-negative breast cancer (TNBC)
Immunophenotypic characterization of lymphocyte components showed that the presence of elevated TILs was positively associated with the density of CD4+ (r = 0.347) and forkhead box protein 3 (FOXP3)+ (r = 0.327) lymphocytes, and the strongest correlation was with CD8+ T cells (r = 0.511; Fig. 1a)
We demonstrated that programmed cell death 1 (PD-1)+ and lymphocyte activation gene 3 (LAG-3)+ TILs were present in approximately 30% and 18% of TNBCs, respectively, and that their presence in the tumor microenvironment tended to be associated with good prognosis in TNBC
Summary
Stromal tumor-infiltrating lymphocytes (TILs) are a robust prognostic factor in triple-negative breast cancer (TNBC). We aimed to evaluate the composition and the functionality of lymphocytic infiltration and checkpoint receptors in TNBC. The presence of tumor-infiltrating lymphocytes (TILs) is emerging as an important predictor of outcome and response to chemotherapy in TNBC [3,4,5,6,7]. Recent findings demonstrate that the expression of immune markers related to immunosuppression is enriched in triple-negative/basal-like breast cancer, and correlate with prognosis and response to chemotherapy, supporting the evaluation of immunotherapy in TNBC [6, 10,11,12,13,14].
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