Anti–CTLA‐4 synergizes with dendritic cell–targeted vaccine to promote IL‐3–dependent CD4+ effector T cell infiltration into murine pancreatic tumors. Issue 1 (4th April 2019)

• Record Type: Journal Article
• Authors: Zaidi, Neeha; Quezada, Sergio A.; Kuroiwa, Janelle M.Y.; Zhang, Li; Jaffee, Elizabeth M.; Steinman, Ralph M.; Wang, Bei
• Is Part Of: Annals of the New York Academy of Sciences. Volume 1445:Issue 1(2019)
• Page Start: 62
• Page End: 73
• Publication Date: 2019-04-04
• Subjects: IL‐3 -- cancer immunotherapy -- anti–CTLA‐4 -- dendritic cell–targeted cancer vaccine -- tumor‐infiltrating T cells; Medical sciences -- Periodicals; Medicine -- Periodicals; Science -- Periodicals; 610
• DOI: 10.1111/nyas.14049
• Languages: English
• ISSNs: 0077-8923

Abstract

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 (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. Abstract : This paper demonstrates that combining anti–CTLA‐4, an immune checkpoint inhibitory antibody used in cancer immunotherapy, with a dendritic cell vaccine triggers an increase in CD4 + effector T cell infiltration into tumors in a mouse pancreatic cancer model, and IL‐3 was identified as a critical mediator of this effect. These findings offer a potential strategy to improve cancer vaccine efficacy.