title: The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Nicolas J
authors.initials: NJ
authors.lastname: Llosa
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Michael
authors.initials: M
authors.lastname: Cruise
authors.affiliation: Flow Cytometry Core, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Ada
authors.initials: A
authors.lastname: Tam
authors.affiliation: Department of Surgery, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Wicks
authors.affiliation: Department of Surgery, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Hechenbleikner
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Janis M
authors.initials: JM
authors.lastname: Taube
authors.affiliation: Flow Cytometry Core, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Blosser
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Hongni
authors.initials: H
authors.lastname: Fan
authors.affiliation: Department of Oncology Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Oncology Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Brandon S
authors.initials: BS
authors.lastname: Luber
authors.affiliation: Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
authors.affiliation: Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.affiliation: Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland. Department of Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Sears
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Anders
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland. Department of Pathology, Johns Hopkins University, Baltimore, Maryland. Department of Medicine, Johns Hopkins University, Baltimore, Maryland. Department of Molecular Biology and Genetics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland. fhousse1@jhmi.edu Dpardol1@jhmi.edu.
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland. fhousse1@jhmi.edu Dpardol1@jhmi.edu.
authors.forename: Franck
authors.initials: F
authors.lastname: Housseau
mesh_terms: D059447:Cell Cycle Checkpoints; D003110:Colonic Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D053842:Microsatellite Instability; D010641:Phenotype; D017154:Stromal Cells / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics* / Q000276:immunology*