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    An immune stratification reveals a subset of PD-1/LAG-3 double-positive triple-negative breast cancers

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    Author
    Bottai, G; Raschioni, C; Losurdo, A; Di Tommaso, L; Tinterri, C; Torrisi, R; Reis-Filho, JS; Roncalli, M; Sotiriou, C; Santoro, A; ...
    Date
    2016-12-03
    Source Title
    Breast Cancer Research
    Publisher
    BMC
    University of Melbourne Author/s
    Loi, Sherene
    Affiliation
    Sir Peter MacCallum Department of Oncology
    Metadata
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    Document Type
    Journal Article
    Citations
    Bottai, G., Raschioni, C., Losurdo, A., Di Tommaso, L., Tinterri, C., Torrisi, R., Reis-Filho, J. S., Roncalli, M., Sotiriou, C., Santoro, A., Mantovani, A., Loi, S. & Santarpia, L. (2016). An immune stratification reveals a subset of PD-1/LAG-3 double-positive triple-negative breast cancers. BREAST CANCER RESEARCH, 18 (1), https://doi.org/10.1186/s13058-016-0783-4.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/257795
    DOI
    10.1186/s13058-016-0783-4
    Abstract
    BACKGROUND: Stromal 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. METHODS: Formalin-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. RESULTS: The 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. CONCLUSIONS: Overall, 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.

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