Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 38, Pages 23684-23694Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2002806117
Keywords
immune checkpoint blockade; tumor immune microenvironment; breast cancer; bilateral tumor model; predictive biomarkers
Categories
Funding
- Ludwig Center at Harvard University
- National Foundation for Cancer Research
- Jane's Trust Foundation
- Advanced Medical Research Foundation
- National Cancer Institute
- National Institutes of Health [P01CA080124, R35-CA197743, R01-CA208205, U01CA224348, R01CA229851, U54CA224088, P01AI039671]
- Innovation in Cancer Informatics Discovery Grant
- Department of Defense Breast Cancer Research Program Innovator Award [W81XWH-10-1-0016]
- Parker Institute for Cancer Immunotherapy
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Immune checkpoint blockade (ICB) is efficacious in many diverse cancer types, but not all patients respond. It is important to understand the mechanisms driving resistance to these treatments and to identify predictive biomarkers of response to provide best treatment options for all patients. Here we introduce a resection and response-assessment approach for studying the tumor microenvironment before or shortly after treatment initiation to identify predictive biomarkers differentiating responders from nonresponders. Our approach builds on a bilateral tumor implantation technique in a murine metastatic breast cancer model (E0771) coupled with anti-PD-1 therapy. Using our model, we show that tumors from mice responding to ICB therapy had significantly higher CD8(+) T cells and fewer Gr1(+)CD11b(+) myeloid-derived suppressor cells (MDSCs) at early time points following therapy initiation. RNA sequencing on the intratumoral CD8(+) T cells identified the presence of T cell exhaustion pathways in nonresponding tumors and T cell activation in responding tumors. Strikingly, we showed that our derived response and resistance signatures significantly segregate patients by survival and associate with patient response to ICB. Furthermore, we identified decreased expression of CXCR3 in nonresponding mice and showed that tumors grown in Cxcr3(-/-) mice had an elevated resistance rate to anti-PD-1 treatment. Our findings suggest that the resection and response tumor model can be used to identify response and resistance biomarkers to ICB therapy and guide the use of combination therapy to further boost the antitumor efficacy of ICB.
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