Caffeine-enhanced anti-tumor activity of anti-PD1 monoclonal antibody

Antibodies targeting PD1 receptor have emerged as a promising therapeutic strategy against multiple types of solid cancers. However, relatively low complete response rates observed with anti-PD1 mAb monotherapy emphasizes the importance of testing new immunotherapeutic combinations. The production of extracellular adenosine in solid tumors was recently identified as a major immunosuppressive pathway, targeting this pathway would enhance the therapeutic activity of anti-PD1 mAbs. In this study, we evaluated the anti-tumor activity and mechanism of action of caffeine and anti-PD1 mAb combination therapy against carcinogen- and cell line-induced tumors. Our results demonstrate that combination therapy enhanced the anti-tumor activity and prolonged overall survival period against 3-MCA-induced tumors. In addition, combination therapy showed a significant anti-tumor activity against B16F10 melanoma tumors. We found that combination therapy showed additive increase in infiltration of CD4+ and CD8+ T lymphocytes into the B16F10 melanoma tumors. On the other hand, combination therapy showed significant decrease in infiltration of CD4+CD25+ T regulatory cells. We further investigated whether the observed anti-tumor effect of caffeine and anti-PD1 mAb combination therapy is mediated through the release of cytokines. We found that caffeine and anti-PD1 mAb combination therapy significantly increased intra-tumoral TNF-α and IFN-γ levels. Our work suggests that administration of caffeine and anti-PD1 mAb harness the therapeutic potential of effector T cells in vivo possibly due to combined blockade of PD1 and adenosine-A2A receptor pathway. This study provides the scientific basis for testing combination regimens of caffeine and anti-PD1 mAbs for sustained tumor control in cancer patients.