Anti–CTLA‐4 synergizes with dendritic cell–targeted vaccine to promote IL‐3–dependent CD4+ effector T cell infiltration into murine pancreatic tumors

Abstract One successful class of cancer immunotherapies, immune checkpoint inhibitory antibodies, disrupts key pathways that regulate immune checkpoints, such as cytotoxic T lymphocyte–associated antigen‐4 (CTLA‐4). These agents unleash the potency of antigen‐experienced T cells that have already been induced as a consequence of the existing tumor. But only 20% of cancers naturally induce T cells. For most cancers, vaccines are require to induce and mobilize T effector cells (T effs ) to traffick into tumors. We evaluated the effects of anti–CTLA‐4 given in combination with an antigen‐specific dendritic cell vaccine on intratumoral T effs in a murine pancreatic cancer model. The dendritic cell–targeted tumor antigen plus anti–CTLA‐4 significantly increased the number of vaccine‐induced CD4 + T effs within the tumor. This increase was accompanied by a reduction in the size of the peripheral CD4 + T eff pool. We also found that IL‐3 production by activated CD4 + T cells was significantly increased with this combination. Importantly, the CD4 + T eff response was attenuated in Il3 −/− mice, suggesting mediation of the effect by IL‐3. Finally, the induced T cell infiltration was associated with activation of the tumor endothelium by T cell–derived IL‐3. Our findings collectively provide a new insight into the mechanism driving T eff infiltration and vascular activation in a murine pancreatic cancer model, specifically identifying a new role for IL‐3 in the anticancer immune response.