Antibodies against the multifaceted cathepsin D protein open new avenues for TNBC immunotherapy

Abstract

Triple-negative breast cancer (TNBC) is a heterogeneous breast cancer subtype characterized by aggressive clinical behavior and poor prognosis. The immune landscape associated with TNBC often reveals high immunogenicity. Therefore, immunotherapy, which has demonstrated its efficacy in different cancer types, could be a promising strategy for TNBC, given the limited therapeutic options currently available besides conventional chemotherapy. The aspartic protease cathepsin D (cath-D) is a tumor cell-associated extracellular protein with protumor activity, a marker of poor prognosis, and a target for antibody-based therapy in TNBC. This commentary provides a synopsis/narrative summary of the development of anti-cath-D antibodies in different formats, their key roles in restoring the antitumor immunity, particularly via activation of tumor-infiltrating natural killer cells, and their dual antitumor effects on cancer cells and stromal cancer-associated fibroblasts, suggesting their interest for clinical use in the light of the current clinical knowledge on TNBC.

Keywords: Antibody; Breast Cancer; Immunomodulation; Immunotherapy; Natural killer - NK.

Figure 1. Antibody targeting the multifaceted cathepsin D protein as a novel clinical opportunity for TNBC immunotherapy. (A) Immunotherapy of TNBC with the F1 anti-cath-D targeting antibody. F1 antitumor response is triggered through NK cell activation via IL15 upregulation, associated with granzyme B and perforin production, and IFNγ release. F1 also prevents the recruitment of M2-TAMs and MDSCs, a specific effect associated with a less immunosuppressive tumor microenvironment highlighted by TGF-β decrease. (B) Anti-cath-D immunotherapy with F1 and F1M1 triggers both innate and adaptive antitumor immunity in an immunocompetent mouse model of TNBC. The F1 and F1M1 antibodies in the mouse IgG2a format promote the innate antitumor immunity by activating NK cells and preventing the recruitment of immunosuppressive M2-TAMs in the tumor microenvironment of C57BL/6 mice harboring E0771 cell grafts. They also enhance activation of antitumor antigen-presenting cells (CD86+ M1-polarized TAMs and cDC1 cells), supporting the reduction of PD-L1+ tolerogenic CD4+ and CD8+ T cells and exhaustion markers, including LAG3 and TIGIT, in the tumor microenvironment. (C) Generation of the Fc-engineered F1M1-Fc+ anti-cath-D antibody as a novel therapeutic opportunity for TNBC. F1M1-Fc+ enhances in vitro NK cell activation and ADCC of both TNBC cells and CAFs. F1M1-Fc+ triggers tumor-infiltrating NK cell recruitment and cytotoxic activity in TNBC. In combination therapies, F1M1-Fc+ improves the therapeutic efficacy of paclitaxel and enzalutamide in TNBC. F1M1-Fc+ enhances in vitro NK cell activation and ADCC of both TNBC cells and CAFs. F1M1-Fc+ triggers tumor-infiltrating NK cell recruitment and cytotoxic activity in TNBC. In combination therapies, F1M1-Fc+ improves the therapeutic efficacy of paclitaxel and enzalutamide in TNBC. ADCC, antibody-dependent cellular cytotoxicity; CAFs, cancer-associated fibroblasts; cath-D, cathepsin D; cDC1, conventional type 1 dendritic cells; GzmB, granzyme B; IFNγ, interferon gamma; IgG, immunoglobulin G; IL15, interleukin-15; MDSCs, myeloid-derived immunosuppressive populations; MHC, major histocompatibility complex; NK, natural killer; PD-L1, programmed death-ligand 1; TAMs, tumor-associated macrophages; TNBC, triple-negative breast cancer.