Targeting CD73 enhances the anti-tumor activity of anti-PD-1 and anti-CTLA-4 mAbs
Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels un blocage ciblé de CD73 renforce l'activité antitumorale d'un anticorps monoclonal anti¨PD-1 ou anti CTLA-4
Purpose: Monoclonal antibodies (mAb) that block programmed death (PD)-1 or cytotoxic T lymphocyte antigen (CTLA-4) receptors have been associated with durable clinical responses against a variety of cancer types and hold great potential as novel cancer therapeutics. Recent evidence suggest that targeted blockade of multiple immunosuppressive pathways can induce synergistic anti-tumor responses. Experimental Design: In this study, we investigated whether targeted blockade of CD73, an ecto-nucleotidase that catabolizes the hydrolysis of extracellular adenosine monophosphate (AMP) to adenosine, can enhance the anti-tumor activity of anti-CTLA-4 and anti-PD-1 mAbs against transplanted and chemically-induced mouse tumors. Results: Anti-CD73 mAb significantly enhanced the activity of both anti-CTLA-4 and anti-PD-1 mAbs against MC38-OVA (colon) and RM-1 (prostate) subcutaneous tumors, and established metastatic 4T1.2 breast cancer. Anti-CD73 mAb also significantly enhanced the activity of anti-PD-1 mAb against 3-methylcholanthrene (MCA)-induced fibrosarcomas. Gene-targeted mice revealed that single agent therapies and combinatorial treatments were dependent on host IFN-gamma and CD8+ T cells, but independent of perforin. Interestingly, anti-CD73 mAb preferentially synergized with anti-PD-1 mAb. We investigated the effect of extracellular adenosine on tumor-infiltrating T cells and demonstrated that activation of A2A adenosine receptor enhances PD-1 expression, but not CTLA-4 expression, on tumor-specific CD8+ T cells and CD4+ Foxp3+ T regulatory cells. Conclusions: Taken together, our study revealed that targeted blockade of CD73 can enhance the therapeutic activity of anti-PD-1 and anti-CTLA-4 mAbs and may thus potentiate therapeutic strategies targeting immune checkpoint inhibitors in general.