Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs

Allard, Bertrand, Pommey, Sandra, Smyth, Mark J. and Stagg, John (2013) Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clinical Cancer Research, 19 20: 5626-5635. doi:10.1158/1078-0432.CCR-13-0545


Author Allard, Bertrand
Pommey, Sandra
Smyth, Mark J.
Stagg, John
Title Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs
Journal name Clinical Cancer Research   Check publisher's open access policy
ISSN 1078-0432
1557-3265
Publication date 2013-10
Year available 2013
Sub-type Article (original research)
DOI 10.1158/1078-0432.CCR-13-0545
Open Access Status
Volume 19
Issue 20
Start page 5626
End page 5635
Total pages 10
Place of publication Philadelphia, United States
Publisher American Association for Cancer Research
Collection year 2014
Language eng
Formatted 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-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.
Keyword T-cell exhaustion
Tumor-infiltrating lymphocytes
Regulatory T
Combination immunotherapy
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Medicine Publications
 
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