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Published on: February 8, 2018
Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs
Bertrand Allard1, Sandra Pommey, Mark J Smyth
1Authors' Affiliations: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Faculté de Pharmacie et Institut du Cancer de Montréal, Montréal, Québec, Canada; Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria; Immunology in Cancer and Infection Laboratory, Queensland Institute of Medical Research; and School of Medicine, University of Queensland, Herston, Queensland, Australia.
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-γ 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 showed 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.
Insights
Blocking CD73 enhances the effectiveness of immune checkpoint inhibitors like anti-PD-1 and anti-CTLA-4 antibodies. This combination therapy shows significant potential for improving cancer treatment outcomes by boosting antitumor responses.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Immune checkpoint inhibitors, such as anti-programmed death (PD)-1 and anti-cytotoxic T lymphocyte antigen (CTLA)-4 monoclonal antibodies (mAbs), offer durable clinical responses in various cancers.
- Targeting multiple immunosuppressive pathways simultaneously may lead to synergistic antitumor effects.
Purpose of the Study:
- To investigate if blocking CD73 can enhance the antitumor activity of anti-CTLA-4 and anti-PD-1 mAbs.
- To evaluate the efficacy of CD73 blockade in combination with established immunotherapies against different tumor models.
Main Methods:
- Utilized anti-CD73, anti-CTLA-4, and anti-PD-1 monoclonal antibodies in transplanted and chemically induced mouse tumor models.
- Employed gene-targeted mice to analyze the roles of IFN-γ and CD8(+) T cells in therapeutic responses.
- Assessed the impact of extracellular adenosine on tumor-infiltrating T cells and immune checkpoint receptor expression.
Main Results:
- Anti-CD73 mAb significantly improved the efficacy of both anti-CTLA-4 and anti-PD-1 mAbs against colon, prostate, and breast cancer models.
- Combinatorial treatment showed dependency on host IFN-γ and CD8(+) T cells.
- CD73 blockade preferentially synergized with anti-PD-1, potentially due to adenosine receptor A2A activation enhancing PD-1 expression on T cells.
Conclusions:
- Targeted blockade of CD73 potentiates the therapeutic activity of anti-PD-1 and anti-CTLA-4 mAbs.
- CD73 inhibition represents a promising strategy to enhance immune checkpoint inhibitor therapies for cancer treatment.
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