Abstract
BackgroundClinical application of cancer immunotherapy requires a better understanding of tumor immunogenicity and the tumor microenvironment. HLA class I molecules present antigens to CD8+ cytotoxic cells. Their loss or downregulation is frequently found in tumors resulting in reduced T cell responses and worse prognosis.MethodsWe evaluated HLA class I heavy chain expression by immunohistochemistry in 863 biopsies (GeparTrio trial). Patients received neoadjuvant chemotherapy and adjuvant endocrine treatment if tumors were hormone receptor-positive (HR+). In parallel, the expression of HLA-A was analyzed using a microarray cohort of 320 breast cancer patients from the MD Anderson Cancer Center. We evaluated its association with clinical outcome, tumor-infiltrating lymphocytes (TILs), and immune cell metagenes.ResultsIn HR+/HER2− breast cancer, HLA class I heavy chain expression was associated with increased TILs and better response to chemotherapy (7% vs. 14% pCR rate, P = 0.029), but worse disease-free survival (hazard ratio (HR) 1.6 (1.1–2.4); P = 0.024). The effect was significant in a multivariate model adjusted for clinical and pathological variables (HR 1.7 (1.1–2.6); P = 0.016) and was confirmed by analysis of HLA-A in a microarray cohort. HLA-A was correlated to most immune cell metagenes. There was no association with response or survival in triple-negative or HER2+ disease.ConclusionsThe study confirms the negative prognostic role of lymphocytes in HR+ breast cancer and points at a complex interaction between chemotherapy, endocrine treatment, and tumor immunogenicity. The results point at a subtype-specific and potentially treatment-specific role of tumor-immunological processes in breast cancer with different implications in triple-negative and hormone receptor-positive disease.
Highlights
Clinical application of cancer immunotherapy requires a better understanding of tumor immunogenicity and the tumor microenvironment
We evaluated expression of Human leucocyte antigen (HLA) class I heavy chains (HC) in a large cohort of breast cancer patients treated with anthracycline/ taxane-based neoadjuvant chemotherapy
HLA class I expression in breast cancer A total of 732 cases from the GeparTrio trial were analyzed for HLA class I HC expression
Summary
Clinical application of cancer immunotherapy requires a better understanding of tumor immunogenicity and the tumor microenvironment. HLA class I molecules present antigens to CD8+ cytotoxic cells. Their loss or downregulation is frequently found in tumors resulting in reduced T cell responses and worse prognosis. Interactions between cancer cells and the host immune system are important for development, evolution, and progression of cancer [1]. They influence response to therapy and survival of patients and modulating these effects offer new approaches for cancer therapy. Evidence suggests a role of the immune system in breast cancer, as the quantity of tumor-infiltrating lymphocytes (TILs) is associated with better response to neoadjuvant chemotherapy and better patient outcome [3, 4]. TILs were associated with a shorter OS in patients with hormone receptor-positive, HER2-negative (HR+/HER2−) disease, pointing at differences according to breast cancer subtype
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