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

Neeha Zaidi, Sergio A Quezada, Janelle M Y Kuroiwa, Li Zhang, Elizabeth M Jaffee, Ralph M Steinman, Bei Wang

Annals of the New York Academy of Sciences 2019 Jun

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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 (Teffs ) to traffick into tumors. We evaluated the effects of anti-CTLA-4 given in combination with an antigen-specific dendritic cell vaccine on intratumoral Teffs in a murine pancreatic cancer model. The dendritic cell-targeted tumor antigen plus anti-CTLA-4 significantly increased the number of vaccine-induced CD4+ Teffs within the tumor. This increase was accompanied by a reduction in the size of the peripheral CD4+ Teff pool. We also found that IL-3 production by activated CD4+ T cells was significantly increased with this combination. Importantly, the CD4+ Teff 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 Teff infiltration and vascular activation in a murine pancreatic cancer model, specifically identifying a new role for IL-3 in the anticancer immune response. © 2019 New York Academy of Sciences.

Citation

Neeha Zaidi, Sergio A Quezada, Janelle M Y Kuroiwa, Li Zhang, Elizabeth M Jaffee, Ralph M Steinman, Bei Wang. Anti-CTLA-4 synergizes with dendritic cell-targeted vaccine to promote IL-3-dependent CD4+ effector T cell infiltration into murine pancreatic tumors. Annals of the New York Academy of Sciences. 2019 Jun;1445(1):62-73