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.

Keywords: IL-3; anti-CTLA-4; cancer immunotherapy; dendritic cell-targeted cancer vaccine; tumor-infiltrating T cells.