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A higher number of HSP70 positive immune cells in a deep layer of TNBC is associated with a higher FOXP3 expression and a higher risk of axillary lymph node involvement

Background: The high mutation burden of triple- negative breast cancer (TNBC) is related to its immunogenic potential. The presence of tumour infiltrating lymphocytes (TILs) in the preclinical stage of disease reflects a proinflammatory immune response against cancer cells. However, cancer cells may modulate it to support tumour growth and progression. A chaperone HSP70 molecule expression, upregulated by oncogenic signal�ling, supports the formation of early-stage breast cancer (BC) as well. Moreover, in the later course of the disease, HSP70 is actively released by the cancer cells and can induce the termination of the specific immune response. The aim of this study was to explore the role and possible predictive value of the HSP70(+) immune cells in a deep layer (HSP70-IC�DL) of TNBC. Material and methods: Clinical data and surgical tissue specimens from 68 consecutive, stage I-III, TNBC patients, submitted to the upfront surgery in Clinical Hospital Centre Rijeka in the period from 2008 till 2016, as well as the 36 control specimens from benign breast tissue biopsies, were included in the present retrospective study. TILs, CD8, CD4, FOXP3, CD68, CD11c, PDL-1, CTLA-4 and HSP70 staining were evaluated in both groups by two independent dedicated breast cytopathologists. Results: In contrast to benign breast tissue, a significantly higher infiltration of all immune cells, including HSP70-IC-DL, was observed in the study group (p < 0.001). The following positive correlations were detected with the respect to the number of HSP70-IC-DL: TILs expression in a both layers (superficial, rho = 0.30, p = 0.025 ; deep, rho = 0.38, p = 0.002), FOXP3 expression in the superficial layer and in the metastasis (rho=0.42, p < 0.001 ; rho = 0.61, p = 0.026) and CTLA-4 expression in a deep layer (rho = 0.34, p = 0.006). Consistent with our previous findings, HSP70-IC-DL is associated with the adverse clinical and pathological markers as well ; higher stage of disease (p = 0.013), higher grade (p = 0.013) and a higher pN status (p < 0.001). The latest association may represent a valuable tool for the prediction of the lymph node involvement (AUC = 0.78, p < 0.001) as well as the lymph node capsular penetration (AUC = 0.78, p < 0.001). Conclusion: Upon the results of our previous analysis and the available literature data, we hypothesized the correlation of HSP70-IC-DL with the cancer-induced immunotolerance in the BC. Herein presented correlations of HSP-IC-DL with the FOXP3 and CTLA-4 expression in TNBC further support our initial findings. Targeting the HSP70 molecule, or the HSP70-related pathways in TNBC could have a role in further immunotherapy development in this BC subtype. In addition, routine evaluation of HSP70- IC-DL may improve clinical decision-making with respect to axillary surgery in TNBC patients. Further translational and clinical research is required to confirm our observations.

triple-negative breast cancer, HSP70, tumour infiltrating lymphocytes, immunohistochemistry, FOXP3

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