Targeting CD73 Enhances the Antitumor Activity of Anti-PD-1 and Anti-CTLA-4 mAbs

Abstract

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 antitumor responses.Experimental Design: In this study, we investigated whether targeted blockade of CD73, an ectonucleotidase that catabolizes the hydrolysis of extracellular adenosine monophosphate (AMP) to adenosine, can enhance the antitumor 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-g and CD8 þ 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 showed that activation of A2A adenosine receptor enhances PD-1 expression, but not CTLA-4 expression, on tumor-specific CD8þ T cells and CD4þ Foxp3þ 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.

Selective activation of anti-CD73 mechanisms in control of primary tumors and metastases

“…9,10,11 Anti-CD73 monotherapy has clinical promise, but studies also indicated that these mAbs effectively synergized with anti-PD-1 or anti-CTLA-4 mAbs. 12 Additionally, our recent findings identified that co-targeting molecules within the adenosinergic pathway displayed a synergistic reduction in the number of lung metastases. Specifically, the combination blockade of CD73 and A2AR provided improved therapeutic efficacy over monotherapy alone, 11 thus reflecting the non-redundant nature of these molecules in mediating antitumor immunity.…”

“…12 We, therefore, assessed whether blocking with 2C5 (mIgG2a) could similarly induce release of IFNg. Similar to TY/23, in vitro addition (Fig.…”

The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27

“…20,21,[32][33][34][35] These studies evidenced the CD39-CD73-adenosine receptor axis blockade as a promising therapeutic target. 31,[36][37][38][39][40][41][42] In line with these studies and with the objective to better understand the mechanism involved in the acquisition by TAM of an immunoregulatory phenotype, this study aimed at evaluating the impact of ATP and ATP metabolites on TAM functions.…”

CD73-adenosine reduces immune responses and survival in ovarian cancer patients

“…6 Moreover, these studies demonstrated that blocking CD73 or A2A adenosine receptor significantly enhanced the antitumor activity of immunecheckpoint therapies. [7][8][9] In cancer patients, high levels of CD73 expression is increasingly reported to be associated with worse outcome in various types of cancers, including triple-negative breast cancer. Until recently, however, the prognostic value of CD73 in ovarian cancer, and in particular in HGSC, was unclear.…”