Abstract
Prediction of breast cancer response to Neoadjuvant Chemotherapy (NACT) is an urgent need to promptly direct non-responder patients to alternative therapies. Infiltrating T lymphocytes, namely cytotoxic T lymphocytes (CTLs) have been appointed as predictors of response. However, cancer cells have the ability to dampen CTLs' activity and thus, the prognostic value of the CTLs, per se, is debatable. Here, we disclose that more than the occurrence of CTLs, it is their activation state, revealed by HLA-DR expression, that can accurately predict response to NACT. Flow cytometry analysis of breast cancer biopsies showed that the frequency of CTLs and other lymphocytes were similar regardless disease stage and between NACT responders and non-responders. However, only breast cancer patients without axillary lymph node metastasis and NACT responders have HLA-DRhi CTLs. Interestingly, HLA-DR levels in tumor CTLs is correlated with HLA-DR levels in systemic CTLs. These HLA-DR+ CTLs produce IFN-γ and Granzyme B, enlightening their effector and probable anti-tumor activity profile. Moreover, the level of HLA-DR in CTLs is negatively correlated with the level of HLA-DR in T regulatory lymphocytes and with immunosuppressive and pro-tumor molecules in the tumor microenvironment. Hence, HLA-DR levels in CTLs is a highly sensitive and specific potential predictive factor of NACT-response, which can be assessed in blood to guide therapeutic decisions.
Highlights
Breast cancer remains one of the main causes of cancer-related deaths in women worldwide [1]
By flow cytometry analysis of fresh samples, we demonstrated that a subset of cytotoxic T lymphocytes (CTLs) expressing HLADR is enriched in breast cancer without axillary lymph node metastasis comparing with breast cancer with axillary lymph node metastasis, the average frequency of CTLs is similar between groups
Some efforts have been made in the past years, such as the introduction of tumor infiltrating lymphocytes (TILs) as possible biomarkers of response, especially in triple negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2)+ breast cancer (BC) [7], there is still no validated biomarker being routinely used in the clinic
Summary
Breast cancer remains one of the main causes of cancer-related deaths in women worldwide [1]. Advances in breast cancer treatment have been made, namely with the introduction of preoperative neoadjuvant chemotherapy (NACT) in selected cases of advanced tumors (with tumor size larger than 2 cm and/or disease extension to axillary lymph node) or inflammatory breast cancer. This treatment is effective in reducing the size of the primary tumor, allowing breast conservation in HLA-DRhi CTLs Predict NACT Response selected cases, and some patients achieve a pathological complete response (pCR) [2]. It is essential to find a good marker of response to NACT, in order to promptly direct patients to alternative therapies, avoiding the misuse of resources and the potential toxicity associated with NACT
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