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

doi:10.1111/bph.16291

Anti-cathepsin D immunotherapy triggers both innate and adaptive anti-tumour immunity in breast cancer

Br J Pharmacol. 2023 Nov 29. doi: 10.1111/bph.16291. Online ahead of print.

Authors

Timothée David¹, Aude Mallavialle¹, Julien Faget¹, Lindsay B Alcaraz¹, Marion Lapierre¹, Pénélope Desroys du Roure¹, Valérie Laurent-Matha¹, Hanane Mansouri^{1

2}, Marta Jarlier³, Pierre Martineau¹, Pascal Roger^{1

4}, Séverine Guiu^{1

5}, Thierry Chardès^{1

6}, Emmanuelle Liaudet-Coopman¹

Affiliations

¹ IRCM, INSERM U1194, Univ Montpellier, ICM, Montpellier, France.
² RHEM, IRCM, Montpellier, France.
³ Biometry Department, ICM, Montpellier, France.
⁴ Department of Pathology, CHU Nîmes, Nîmes, France.
⁵ Department of Medical Oncology, ICM, Montpellier, France.
⁶ Centre national de la recherche Scientifique, CNRS, Paris, France.

PMID: 38030588
DOI: 10.1111/bph.16291

Abstract

Background and purpose: Triple-negative breast cancer (TNBC) has poorer outcomes than other breast cancers (BC), including HER2⁺ BC. Cathepsin D (CathD) is a poor prognosis marker overproduced by BC cells, hypersecreted in the tumour microenvironment with tumour-promoting activity. Here, we characterized the immunomodulatory activity of the anti-CathD antibody F1 and 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. Antibody anti-tumour efficacy was investigated in mouse models. Immune cell recruitment and activation were assessed by immunohistochemistry, immunophenotyping, and RT-qPCR.

Key results: F1 and F1M1 antibodies remodelled the tumour immune landscape. Both antibodies promoted 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.

Keywords: TNBC; anti-tumour immunity; antibody-based therapy; breast cancer; immunomodulation; protease; tumour microenvironment.

Abstract

Grants and funding