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
StatePublished - Jan 1 2019

Fingerprint

T-cells
Interleukin-3
Infiltration
Tumors
Vaccines
T-Lymphocytes
Neoplasms
Chemical activation
Pancreatic Neoplasms
Cancer Vaccines
Viral Tumor Antigens
Neoplasm Antigens
Antigens
Immunotherapy
Dendritic Cells
Endothelium
Blood Vessels
Vaccine
Cells
Antibodies

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

Anti–CTLA-4 synergizes with dendritic cell–targeted vaccine to promote IL-3–dependent CD4 + effector T cell infiltration into murine pancreatic tumors . / Zaidi, Neeha; Quezada, Sergio A.; Kuroiwa, Janelle M.Y.; Zhang, Li; Jaffee, Elizabeth; Steinman, Ralph M.; Wang, Bei.

In: Annals of the New York Academy of Sciences, 01.01.2019.

Research output: Contribution to journalArticle

@article{c5265522675042e1ad0de8863643736f,
title = "Anti–CTLA-4 synergizes with dendritic cell–targeted vaccine to promote IL-3–dependent CD4 + effector T cell infiltration into murine pancreatic tumors",
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.",
keywords = "anti–CTLA-4, cancer immunotherapy, dendritic cell–targeted cancer vaccine, IL-3, tumor-infiltrating T cells",
author = "Neeha Zaidi and Quezada, {Sergio A.} and Kuroiwa, {Janelle M.Y.} and Li Zhang and Elizabeth Jaffee and Steinman, {Ralph M.} and Bei Wang",
year = "2019",
month = "1",
day = "1",
doi = "10.1111/nyas.14049",
language = "English (US)",
journal = "Annals of the New York Academy of Sciences",
issn = "0077-8923",
publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - Anti–CTLA-4 synergizes with dendritic cell–targeted vaccine to promote IL-3–dependent CD4 + effector T cell infiltration into murine pancreatic tumors

AU - Zaidi, Neeha

AU - Quezada, Sergio A.

AU - Kuroiwa, Janelle M.Y.

AU - Zhang, Li

AU - Jaffee, Elizabeth

AU - Steinman, Ralph M.

AU - Wang, Bei

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - anti–CTLA-4

KW - cancer immunotherapy

KW - dendritic cell–targeted cancer vaccine

KW - IL-3

KW - tumor-infiltrating T cells

UR - http://www.scopus.com/inward/record.url?scp=85063802229&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85063802229&partnerID=8YFLogxK

U2 - 10.1111/nyas.14049

DO - 10.1111/nyas.14049

M3 - Article

C2 - 30945313

AN - SCOPUS:85063802229

JO - Annals of the New York Academy of Sciences

JF - Annals of the New York Academy of Sciences

SN - 0077-8923

ER -