HLA-DR in Cytotoxic T Lymphocytes Predicts Breast Cancer Patients' Response to Neoadjuvant Chemotherapy

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.

Deciphering the complex circulating immune cell microenvironment in chronic lymphocytic leukemia using patient similarity networks

“…Interestingly, some our patients on novel agents had a very low HLA-DR expression on immune cells. Since HLA-DR expression on immune cells may re ect the response to the therapy as shown in breast cancer patients [28], our patients on novel drugs with low immune cell activation may have a high risk of disease progression, as shown in some cases. Interestingly, our data showed different time-dependent dynamics of immune cell activation and redistribution of CLL cells from tissues to peripheral blood when treated with ibrutinib and idelalisib, respectively.…”

“…Moreover, HLA-DR expression on leukemic cells was suggested to be essential for establishing effective antitumor immunity via CD4 + cell activation and the recruitment of effector cell populations, such as macrophages [27]. Besides being an important prognostic marker on tumor cells, HLA-DR expression on immune cells has been shown to re ect the tumor immune status and the response to the therapy [28]. In line with the above evidence, we suggested that HLA-DR expression may re ect disease progression and the treatment response in CLL as well.…”

Dynamic Biomarkers Indicate Immunological Benefits Provided by Ganoderma Spore Powder in Post-Operative Breast and Lung Cancer Patients: A Prospective Clinical Trial

“…HLA-DR, as a T lymphocyte immune-regulatory molecule has been shown to vary during the cancer progression [28]. Saraiva et al, demonstrated that HLA-DR + expression signi cantly declined in cancer subjects and is strongly connected with prognosis [29][30], as reported in 67% of gastric cancer cases and in 80% of poorly differentiated adenocarcinoma [31]. Intriguingly, our study showed that HLA-DR co-expression in CD3, CD4 and CD8 subsets was a signi cant trend towards suppression of drug stimuli.…”

Deciphering The Complex Circulating Immune Cell Microenvironment in Chronic Lymphocytic Leukemia Using Patient Similarity Networks

“…Interestingly, some our patients on novel agents had a very low HLA-DR expression on immune cells. Since HLA-DR expression on immune cells may reflect the response to the therapy as shown in breast cancer patients [28], our patients on novel drugs with low immune cell activation may have a high risk of disease progression, as shown in some cases. Interestingly, our data showed different time-dependent dynamics of immune cell activation and redistribution of CLL cells from tissues to peripheral blood when treated with ibrutinib and idelalisib, respectively.…”

“…Moreover, HLA-DR expression on leukemic cells was suggested to be essential for establishing effective antitumor immunity via CD4+ cell activation and the recruitment of effector cell populations, such as macrophages [27]. Besides being an important prognostic marker on tumor cells, HLA-DR expression on immune cells has been shown to reflect the tumor immune status and the response to the therapy [28]. In line with the above evidence, we suggested that HLA-DR expression may reflect disease progression and the treatment response in CLL as well.…”