Anti‐cathepsin D immunotherapy triggers both innate and adaptive anti‐tumour immunity in breast cancer
Timothée David, Aude Mallavialle, Julien Faget, Lindsay B. Alcaraz, Marion Lapierre, Pénélope Desroys du Roure, Valérie Laurent‐Matha, Hanane Mansouri, Marta Jarlier, Pierre Martineau, Pascal Roger, Séverine Guiu, Thierry Chardès, Emmanuelle Liaudet‐Coopman- Pharmacology
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.