Journal
CANCER DISCOVERY
Volume 5, Issue 1, Pages 43-51Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-14-0863
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Funding
- NIH [P50 CA062924, RO1 CA151393, K08 DK087856, 5T32CA126607-05, P30 DK089502, P30 CA006973]
- American Society of Colon and Rectal Surgeons [GSRRIG-015]
- Merieux Foundation
- Stand Up To Cancer-Cancer Research Institute Cancer Immunology Dream Team Translational Research (Stand Up To Cancer is a program of the Entertainment Industry Foundation) [SU2C-AACR-DT1012]
- Melanoma Research Alliance award
- Commonwealth Foundation
- Virginia and D.K. Ludwig Fund for Cancer Research
- Ludwig Institute
- NATIONAL CANCER INSTITUTE [P30CA006973, R01CA151393, P50CA062924, T32CA126607, T32CA060441] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [K08DK087856, P30DK089502] Funding Source: NIH RePORTER
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We examined the immune microenvironment of primary colorectal cancer using immunohistochemistry, laser capture microdissection/qRT-PCR, flow cytometry, and functional analysis of tumor-infiltrating lymphocytes. A subset of colorectal cancer displayed high infiltration with activated CD8(+) cytotoxic T lymphocyte (CTL) as well as activated Th1 cells characterized by IFN gamma production and the Th1 transcription factor TBET. Parallel analysis of tumor genotypes revealed that virtually all of the tumors with this active Th1/CTL microenvironment had defects in mismatch repair, as evidenced by microsatellite instability (MSI). Counterbalancing this active Th1/CTL microenvironment, MSI tumors selectively demonstrated highly upregulated expression of multiple immune checkpoints, including five-PD-1, PD-L1, CTLA-4, LAG-3, and IDO-currently being targeted clinically with inhibitors. These findings link tumor genotype with the immune microenvironment, and explain why MSI tumors are not naturally eliminated despite a hostile Th1/CTL microenvironment. They further suggest that blockade of specific checkpoints may be selectively efficacious in the MSI subset of colorectal cancer. SIGNIFICANCE: The findings reported in this article are the first to demonstrate a link between a genetically defined subtype of cancer and its corresponding expression of immune checkpoints in the tumor microenvironment. The mismatch repair-defective subset of colorectal cancer selectively upregulates at least five checkpoint molecules that are targets of inhibitors currently being clinically tested. (C)2014 AACR.
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