TY - JOUR
T1 - TLR1/2 ligand enhances antitumor efficacy of CTLA-4 blockade by increasing intratumoral Treg depletion
AU - Sharma, Naveen
AU - Vacher, Jean
AU - Allison, James P.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Dr. Jeffrey V. Ravetch for providing FcγRIV KO mice, Dr. Andrew C. Chan for providing the anti-CD20 monoclonal antibody, Dr. David Tuveson for providing the mT5 cell line, Dr. Sreyashi Basu for helping with acquiring nanostring data, Nana-Ama A. Anang for providing technical assistance, and Dr. James Jeffrey Mancuso for reading and editing the manuscript. This work was supported by the Cancer Prevention Research Institute of Texas through Grant R1203 (to J.P.A.). J.V.’s laboratory is supported by funding from Canadian Institutes of Health Grant 86655.
Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019
Y1 - 2019
N2 - Canada, and approved April 16, 2019 (received for review November 5, 2018) Immune checkpoint inhibitors such as anti-CTLA-4 antibody are widely accepted therapeutic options for many cancers, but there is still a considerable gap in achieving their full potential. We explored the potential of activating the innate and adaptive immune pathways together to improve tumor reduction and survival outcomes. We treated a mouse model of melanoma with intratumoral injections of Toll-like receptor 1/2 (TLR1/2) ligand Pam3CSK4 plus i.p. injections of anti-CTLA-4 antibody. This combination treatment enhanced antitumor immune responses both qualitatively and quantitatively over anti-CTLA-4 alone, and its efficacy depended on CD4 T cells, CD8 T cells, Fcγ receptor IV, and macrophages. Interestingly, our results suggest a unique mechanism by which TLR1/2 ligand increased Fcγ receptor IV expression on macrophages, leading to antibody-dependent macrophage-mediated depletion of regulatory T cells in the tumor microenvironment and increasing efficacy of anti-CTLA-4 antibody in the combination treatment. This mechanism could be harnessed to modulate the clinical outcome of anti-CTLA- 4 antibodies and possibly other antibody-based immunotherapies.
AB - Canada, and approved April 16, 2019 (received for review November 5, 2018) Immune checkpoint inhibitors such as anti-CTLA-4 antibody are widely accepted therapeutic options for many cancers, but there is still a considerable gap in achieving their full potential. We explored the potential of activating the innate and adaptive immune pathways together to improve tumor reduction and survival outcomes. We treated a mouse model of melanoma with intratumoral injections of Toll-like receptor 1/2 (TLR1/2) ligand Pam3CSK4 plus i.p. injections of anti-CTLA-4 antibody. This combination treatment enhanced antitumor immune responses both qualitatively and quantitatively over anti-CTLA-4 alone, and its efficacy depended on CD4 T cells, CD8 T cells, Fcγ receptor IV, and macrophages. Interestingly, our results suggest a unique mechanism by which TLR1/2 ligand increased Fcγ receptor IV expression on macrophages, leading to antibody-dependent macrophage-mediated depletion of regulatory T cells in the tumor microenvironment and increasing efficacy of anti-CTLA-4 antibody in the combination treatment. This mechanism could be harnessed to modulate the clinical outcome of anti-CTLA- 4 antibodies and possibly other antibody-based immunotherapies.
KW - CTLA-4
KW - TLR1/2 ligand
KW - anti-CTLA-4 antibody
KW - melanoma
KW - tumor immunotherapy
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U2 - 10.1073/pnas.1819004116
DO - 10.1073/pnas.1819004116
M3 - Article
C2 - 31076558
AN - SCOPUS:85066101678
SN - 0027-8424
VL - 116
SP - 10453
EP - 10462
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 21
ER -