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 - Tập 1445 Số 1 - Trang 62-73 - 2019
Neeha Zaidi1,2, Sergio A. Quezada3, Janelle Kuroiwa1, Li Zhang1, Elizabeth M. Jaffee2, Ralph M. Steinman1,4, Bei Wang1
1Laboratory of Cellular Physiology and Immunology and Chris Browne Center of Immunology and Immune Disease, The Rockefeller University, New York City, New York
2The Sidney Kimmel Comprehensive Cancer Center, The Skip Viragh Center for Pancreatic Cancer, The Bloomberg–Kimmel Institute for Cancer Immunotherapy The Johns Hopkins University School of Medicine Baltimore Maryland
3Research Department of Haematology, University College London Cancer Institute, London, UK
4R.M. Steinman passed away on September 30th, 2011.

Tóm tắt

AbstractOne 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.

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Annals of the New York Academy of Sciences

Tập 1445 Số 1

62-73

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