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

摘要: We examined the immune microenvironment of primary colorectal cancer using immunohistochemistry, laser capture microdissection/qRT-PCR, flow cytometry, and functional analysis tumor-infiltrating lymphocytes. A subset displayed high infiltration with activated CD8+ cytotoxic T lymphocyte (CTL) as well Th1 cells characterized by IFNγ production transcription factor TBET. Parallel tumor genotypes revealed that virtually all tumors this active Th1/CTL had defects in mismatch repair, evidenced microsatellite instability (MSI). Counterbalancing microenvironment, MSI selectively demonstrated highly upregulated expression multiple checkpoints, including five—PD-1, PD-L1, CTLA-4, LAG-3, IDO—currently being targeted clinically inhibitors. These findings link genotype explain why are not naturally eliminated despite a hostile microenvironment. They further suggest blockade specific checkpoints may be efficacious cancer. Significance: The reported article first to demonstrate between genetically defined subtype its corresponding repair–defective upregulates at least five checkpoint molecules targets inhibitors currently tested. Cancer Discov; 5(1); 43–51. ©2014 AACR. See related commentary Xiao Freeman, [p. 16][1] This is highlighted In This Issue feature, 1][2] [1]: /lookup/volpage/5/16?iss=1 [2]: /lookup/volpage/5/1?iss=1