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 Jaffee, Ralph M. Steinman, Bei Wang

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalAnnals of the New York Academy of Sciences
DOIs
Publication statusPublished - Jan 1 2019

    Fingerprint

Keywords

  • anti–CTLA-4
  • cancer immunotherapy
  • dendritic cell–targeted cancer vaccine
  • IL-3
  • tumor-infiltrating T cells

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

Cite this