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 M.
AU - Steinman, Ralph M.
AU - Wang, Bei
N1 - Funding Information:
Through a licensing agreement with AduroBiotech, E.M.J. and the Johns Hopkins University receive milestone payments and have the ability to receive royalties on two cancer vaccines in the future. E.M.J. receives grant funding and reagents from Bristol-Myers Squibb, Lustgarten Foundation, AduroBiotech, and Amgen. E.M.J. serves on the SABs of Genocea, DragonFly, Adaptive Biotech, CSTONE, Lustgarten Foundation, Cancer Research Institute, and the Parker Institute. All other authors declare no competing interests.
Funding Information:
This work was supported by grants from the National Institute of Health, NIAID AI13013, P01A1081677, and AI051573; National Center for Advancing Translational Sciences, UL1 TR000043. N.Z. was a Howard Hughes Medical Institute (HHMI) Medical Research Fellow at the Steinman Laboratory at the time. We would like to thank H. Zebroski for synthesizing peptide libraries and J. Adams for graphic editing.
Publisher Copyright:
© 2019 New York Academy of Sciences.
PY - 2019/6
Y1 - 2019/6
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 (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.
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 (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.
KW - IL-3
KW - anti–CTLA-4
KW - cancer immunotherapy
KW - dendritic cell–targeted cancer vaccine
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
SN - 0077-8923
VL - 1445
SP - 62
EP - 73
JO - Annals of the New York Academy of Sciences
JF - Annals of the New York Academy of Sciences
IS - 1
ER -