We have therefore revealed a potentially novel biomarker for the efficacy of anti-PD-1 that warrants further investigation in patients. Because our studies used SYN-115, a drug that has already undergone phase IIb testing in Parkinson disease, our findings have immediate translational relevance for patients with cancer.

Immunotherapy is widely accepted as a powerful new treatment modality for the treatment of cancer. The most successful form of immunotherapy to date has been the blockade of the immune checkpoints PD-1 and CTLA-4. Combining inhibitors of both PD-1 and CTLA-4 increases the proportion of patients who respond to immunotherapy. However, most patients still do not respond to checkpoint inhibitors, and prognostic biomarkers are currently lacking. Therefore, a better understanding of the mechanism by which these checkpoint inhibitors enhance antitumor immune responses is required to more accurately predict which patients are likely to respond and further enhance this treatment modality. Our current study of two mouse tumor models revealed that CD4þ

The specific targeting of tumor-elicited immunosuppression is a promising strategy for the treatment of cancer. We have recently demonstrated that targeting the immunosuppressive pathway mediated by CD73-derived adenosine through the blockade of A2A/A2B adenosine receptors significantly reduced the metastatic potential of CD73+ breast carcinomas and melanomas via both immunological and non-immunological mechanisms.

In our recent study, we show that tumoral CD73 expression limits the efficacy of anti-PD-1 therapy, and this is rescued by concomitant A 2A blockade. Since CD73 is known to be overexpressed in several human cancers and A 2A antagonists have undergone clinical trials for Parkinson's Disease, this combination warrants further investigation.

<p>Supplementary Figure 2</p>

<p>Supplementary Figure 5</p>

<p>Supplementary Figure 1</p>

<p>Supplementary Figure 3</p>