Chen et al. show that adenosine A2B receptor (A2BR) signaling on APCs suppresses antitumor T cell response and promotes tumor growth and metastasis. Compared to WT, A2BR KO inhibited tumor growth in syngeneic tumor models and increased infiltration of tumor antigen-specific and IFNγ-secreting CD8+ T cells. Specific deletion of A2BR in all hematopoietic cells, but not in CD8+ T cells, similarly inhibited tumor growth. A2BR-deficient myeloid APCs expressed elevated levels of activation and maturation markers and enhanced priming and activation of CD8+ T cells. A2BR inhibition enhanced the antitumor effect of adoptive T cell therapy.
Contributed by Shishir Pant
ABSTRACT: Accumulating evidence suggests that inhibiting adenosine-generating ecto-enzymes (CD39 and CD73) and/or adenosine A2A or A2B receptors (R) stimulates antitumor immunity and limits tumor progression. Although activating A2ARs or A2BRs causes similar immunosuppressive and protumoral functions, few studies have investigated the distinct role of A2BR in cancer. Here, we showed that A2BR expression by hematopoietic cells was primarily responsible for promoting tumor growth. Deletion of A2BR profoundly enhanced anticancer T cell immunity. Although T cell A2BR plays an insignificant role for A2BR-mediated immunosuppression and tumor promotion, A2BR deficiency in tumor-bearing mice caused increased infiltration of myeloid and CD103+ dendritic cells, which was associated with more effective cross-priming of adoptively transferred tumor antigen-specific CD8+ T cells. A2BR deletion also intrinsically favored accumulation of myeloid and CD11bdim antigen presenting cells (APCs) in the tumor microenvironment. Both myeloid-specific or CD11c-specific conditional deletion of A2BR delayed primary tumor growth. Myeloid, but not CD11c-specific conditional, depletion delayed lung metastasis. Pharmacological blockade of A2BR improved the antitumor effect of adoptive T cell therapy. Overall, these results suggested that A2BR-expression on myeloid cells and antigen presenting cells indirectly suppressed CD8+ T cell responses and promoted metastasis. These data provide a strong rationale to combine A2BR inhibition with T cell-based immunotherapy for the treatment of tumor growth and metastasis.