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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)62-73
Number of pages12
JournalAnnals of the New York Academy of Sciences
Volume1445
Issue number1
DOIs
StatePublished - Jun 2019

Keywords

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

ASJC Scopus subject areas

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

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