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Anti-cathepsin D immunotherapy triggers both innate and adaptive anti-tumour immunity in breast cancer. Anti-cathepsin D immunotherapy triggers both innate and adaptive anti-tumour immunity in breast cancer: Antibody-based immunomodulatory therapy of breast cancer
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International audience. Background and purpose: Triple-negative breast cancer (TNBC) has poorer outcomes than other breast cancer (BC) subtypes, including HER2+ BC. Cathepsin D (CathD) is a poor prognosis marker overproduced by BC cells and hypersecreted in the tumour microenvironment with tumour-promoting activity. Here, we characterized the immunomodulatory activity of the anti-CathD antibody F1 and of its improved Fab-aglycosylated version (F1M1) in immunocompetent mouse models of TNBC (C57BL/6 mice harbouring E0771 cell grafts) and HER2-amplified BC (BALB/c mice harbouring TUBO cell grafts).Experimental approach: CathD expression was evaluated by western blotting and immunofluorescence, and antibody binding to CathD by ELISA. The antibody anti-tumour efficacy was investigated in mouse models. Immune cell recruitment and activation were assessed by immunohistochemistry, immunophenotyping, and RT-qPCR.Key results: Both F1 and F1M1 antibodies remodelled the tumour immune landscape. Both antibodies promoted the innate antitumour immunity by preventing the recruitment of immunosuppressive M2-polarized tumour-associated macrophages (TAMs) and by activating natural killer cells in the tumour microenvironment of both models. This translated into a reduction of T-cell exhaustion markers in the tumour microenvironment that could be locally supported by enhanced activation of anti-tumour antigen-presenting cell (M1-polarized TAMs and cDC1 cells) functions. Both antibodies inhibited tumour growth in the highly-immunogenic E0771 model, but only marginally in the immune-excluded TUBO model, indicating that anti-CathD immunotherapy is more relevant for BC with a high immune cell infiltrate, as often observed in TNBC.Conclusion and implication: Anti-CathD antibody-based therapy triggers the anti-tumour innate and adaptive immunity in preclinical models of BC, and is a promising immunotherapy for immunogenic TNBC.
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