Статья

The Vigorous Immune Microenvironment of Microsatellite Instable Colon Cancer Is Balanced by Multiple Counter-Inhibitory Checkpoints

Nicolás J. Llosa1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MarylandMichael Cruise2Department of Pathology, Johns Hopkins University, Baltimore, MarylandAda Tam3Flow Cytometry Core, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MarylandElizabeth C. Wicks4Department of Surgery, Johns Hopkins University, Baltimore, MarylandElizabeth M. Hechenbleikner4Department of Surgery, Johns Hopkins University, Baltimore, MarylandJanis M. Taube2Department of Pathology, Johns Hopkins University, Baltimore, MarylandRichard L. Blosser3Flow Cytometry Core, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MarylandHongni Fan1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MarylandHao Wang5Department of Oncology Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MarylandBrandon Luber5Department of Oncology Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MarylandMing Zhang6Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MarylandNickolas Papadopoulos6Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MarylandKenneth W. Kinzler6Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MarylandBert Vogelstein6Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MarylandCynthia L. Sears1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MarylandRobert A. Anders2Department of Pathology, Johns Hopkins University, Baltimore, MarylandDrew M. Pardoll1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MarylandFranck Housseau1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland

2014en

ABI

Аннотация

UNLABELLED: 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 IFNγ 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.

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Идентификаторы

DOI: 10.1158/2159-8290.cd-14-0863

Цитирования и источники

Цитирований: 2Использованных источников: 0

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