Differences in Tumor Microenvironment Dictate T Helper Lineage Polarization and Response to Immune Checkpoint Therapy

Shiping Jiao; Sumit K. Subudhi; Ana Aparicio; Zhongqi Ge; Baoxiang Guan; Yuji Miura; Padmanee Sharma

doi:10.1016/j.cell.2019.10.029

Differences in Tumor Microenvironment Dictate T Helper Lineage Polarization and Response to Immune Checkpoint Therapy

Shiping Jiao, Sumit K. Subudhi, Ana Aparicio, Zhongqi Ge, Baoxiang Guan, Yuji Miura, Padmanee Sharma

Research output: Contribution to journal › Article › peer-review

243 Scopus citations

Abstract

Immune checkpoint therapy (ICT) shows encouraging results in a subset of patients with metastatic castration-resistant prostate cancer (mCRPC) but still elicits a sub-optimal response among those with bone metastases. Analysis of patients’ bone marrow samples revealed increased T_h17 instead of T_h1 subsets after ICT. To further evaluate the different tumor microenvironments, we injected mice with prostate tumor cells either subcutaneously or intraosseously. ICT in the subcutaneous CRPC model significantly increases intra-tumoral T_h1 subsets and improves survival. However, ICT fails to elicit an anti-tumor response in the bone CRPC model despite an increase in the intra-tumoral CD4 T cells, which are polarized to T_h17 rather than T_h1 lineage. Mechanistically, tumors in the bone promote osteoclast-mediated bone resorption that releases TGF-β, which restrains T_h1 lineage development. Blocking TGF-β along with ICT increases T_h1 subsets and promotes clonal expansion of CD8 T cells and subsequent regression of bone CRPC and improves survival.

Original language	English (US)
Pages (from-to)	1177-1190.e13
Journal	Cell
Volume	179
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2019.10.029
State	Published - Nov 14 2019

Keywords

T1 subset
TGF-β blockade
anti-CTLA-4
anti-PD-1
bone metastases
castration-resistant prostate cancer

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

MD Anderson CCSG core facilities

Advanced Technology Genomics Core
Flow Cytometry and Cellular Imaging Facility
Research Animal Support Facility
Small Animal Imaging Facility
Tissue Biospecimen and Pathology Resource

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10.1016/j.cell.2019.10.029

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@article{f08f8ffaafd746fca949aa01c019bd50,

title = "Differences in Tumor Microenvironment Dictate T Helper Lineage Polarization and Response to Immune Checkpoint Therapy",

abstract = "Immune checkpoint therapy (ICT) shows encouraging results in a subset of patients with metastatic castration-resistant prostate cancer (mCRPC) but still elicits a sub-optimal response among those with bone metastases. Analysis of patients{\textquoteright} bone marrow samples revealed increased Th17 instead of Th1 subsets after ICT. To further evaluate the different tumor microenvironments, we injected mice with prostate tumor cells either subcutaneously or intraosseously. ICT in the subcutaneous CRPC model significantly increases intra-tumoral Th1 subsets and improves survival. However, ICT fails to elicit an anti-tumor response in the bone CRPC model despite an increase in the intra-tumoral CD4 T cells, which are polarized to Th17 rather than Th1 lineage. Mechanistically, tumors in the bone promote osteoclast-mediated bone resorption that releases TGF-β, which restrains Th1 lineage development. Blocking TGF-β along with ICT increases Th1 subsets and promotes clonal expansion of CD8 T cells and subsequent regression of bone CRPC and improves survival.",

keywords = "T1 subset, TGF-β blockade, anti-CTLA-4, anti-PD-1, bone metastases, castration-resistant prostate cancer",

author = "Shiping Jiao and Subudhi, {Sumit K.} and Ana Aparicio and Zhongqi Ge and Baoxiang Guan and Yuji Miura and Padmanee Sharma",

note = "Funding Information: We thank the Immunotherapy Platform at MD Anderson Cancer Center for assistance with the clinical trial samples. We thank Drs. Qing Xiong and Hao Zhao for their bioinformatics input. Dr. Sharma is a member of the Parker Institute for Cancer Immunotherapy and the co-director of the Parker Institute for Cancer Immunotherapy at MD Anderson Cancer Center. Supervision and Study Oversight, P.S.; Methodology, P.S. and S.J.; Investigation, S.J.; Software, Formal Analysis, and Visualization, P.S. S.J. and Z.G.; Writing, Review, & Editing, P.S. S.J. S.K.S. A.A. and Z.G.; Funding Acquisition, P.S.; Resources, P.S. S.J. S.K.S. A.A. Z.G. B.G. and Y.M. Dr. Sharma has ownership in Jounce, Neon, Constellation, Oncolytics, BioAtla, Forty-Seven, Apricity, Polaris, Marker Therapeutics, Codiak, ImaginAb, Dragonfly, Lytix, and Hummingbird. Dr. Sharma serves as a consultant for Constellation, Jounce, Neon, BioAtla, Pieris Pharmaceuticals, Oncolytics Biotech, Forty-Seven, Polaris, Apricity, Marker Therapeutics, Codiak, ImaginAb, Dragonfly, Lytix, and Hummingbird. None of the current relationships are related to the study in the manuscript. The other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = nov,

day = "14",

doi = "10.1016/j.cell.2019.10.029",

language = "English (US)",

volume = "179",

pages = "1177--1190.e13",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "5",

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TY - JOUR

T1 - Differences in Tumor Microenvironment Dictate T Helper Lineage Polarization and Response to Immune Checkpoint Therapy

AU - Jiao, Shiping

AU - Subudhi, Sumit K.

AU - Aparicio, Ana

AU - Ge, Zhongqi

AU - Guan, Baoxiang

AU - Miura, Yuji

AU - Sharma, Padmanee

N1 - Funding Information: We thank the Immunotherapy Platform at MD Anderson Cancer Center for assistance with the clinical trial samples. We thank Drs. Qing Xiong and Hao Zhao for their bioinformatics input. Dr. Sharma is a member of the Parker Institute for Cancer Immunotherapy and the co-director of the Parker Institute for Cancer Immunotherapy at MD Anderson Cancer Center. Supervision and Study Oversight, P.S.; Methodology, P.S. and S.J.; Investigation, S.J.; Software, Formal Analysis, and Visualization, P.S. S.J. and Z.G.; Writing, Review, & Editing, P.S. S.J. S.K.S. A.A. and Z.G.; Funding Acquisition, P.S.; Resources, P.S. S.J. S.K.S. A.A. Z.G. B.G. and Y.M. Dr. Sharma has ownership in Jounce, Neon, Constellation, Oncolytics, BioAtla, Forty-Seven, Apricity, Polaris, Marker Therapeutics, Codiak, ImaginAb, Dragonfly, Lytix, and Hummingbird. Dr. Sharma serves as a consultant for Constellation, Jounce, Neon, BioAtla, Pieris Pharmaceuticals, Oncolytics Biotech, Forty-Seven, Polaris, Apricity, Marker Therapeutics, Codiak, ImaginAb, Dragonfly, Lytix, and Hummingbird. None of the current relationships are related to the study in the manuscript. The other authors declare no competing interests. Publisher Copyright: © 2019 Elsevier Inc.

PY - 2019/11/14

Y1 - 2019/11/14

N2 - Immune checkpoint therapy (ICT) shows encouraging results in a subset of patients with metastatic castration-resistant prostate cancer (mCRPC) but still elicits a sub-optimal response among those with bone metastases. Analysis of patients’ bone marrow samples revealed increased Th17 instead of Th1 subsets after ICT. To further evaluate the different tumor microenvironments, we injected mice with prostate tumor cells either subcutaneously or intraosseously. ICT in the subcutaneous CRPC model significantly increases intra-tumoral Th1 subsets and improves survival. However, ICT fails to elicit an anti-tumor response in the bone CRPC model despite an increase in the intra-tumoral CD4 T cells, which are polarized to Th17 rather than Th1 lineage. Mechanistically, tumors in the bone promote osteoclast-mediated bone resorption that releases TGF-β, which restrains Th1 lineage development. Blocking TGF-β along with ICT increases Th1 subsets and promotes clonal expansion of CD8 T cells and subsequent regression of bone CRPC and improves survival.

AB - Immune checkpoint therapy (ICT) shows encouraging results in a subset of patients with metastatic castration-resistant prostate cancer (mCRPC) but still elicits a sub-optimal response among those with bone metastases. Analysis of patients’ bone marrow samples revealed increased Th17 instead of Th1 subsets after ICT. To further evaluate the different tumor microenvironments, we injected mice with prostate tumor cells either subcutaneously or intraosseously. ICT in the subcutaneous CRPC model significantly increases intra-tumoral Th1 subsets and improves survival. However, ICT fails to elicit an anti-tumor response in the bone CRPC model despite an increase in the intra-tumoral CD4 T cells, which are polarized to Th17 rather than Th1 lineage. Mechanistically, tumors in the bone promote osteoclast-mediated bone resorption that releases TGF-β, which restrains Th1 lineage development. Blocking TGF-β along with ICT increases Th1 subsets and promotes clonal expansion of CD8 T cells and subsequent regression of bone CRPC and improves survival.

KW - T1 subset

KW - TGF-β blockade

KW - anti-CTLA-4

KW - anti-PD-1

KW - bone metastases

KW - castration-resistant prostate cancer

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U2 - 10.1016/j.cell.2019.10.029

DO - 10.1016/j.cell.2019.10.029

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AN - SCOPUS:85074688420

SN - 0092-8674

VL - 179

SP - 1177-1190.e13

JO - Cell

JF - Cell

IS - 5

ER -

Differences in Tumor Microenvironment Dictate T Helper Lineage Polarization and Response to Immune Checkpoint Therapy

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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