The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints
By Nicolas L Losa, M. Cruise, Ada Tam, Elizabeth C. Wick, Elizabeth M. Hechenbleikner, Janis M Taube, R. Blosser, H. Fan, Hao Wang, Brandon S. Luber and 9 more. Journal of Immunotherapy for Cancer, 2014
1,370 citations recorded by the source corpus.
We examined the immune microenvironment of primary colorectal cancer (CRC) using immunohistochemistry, laser capture microdissection/qRT-PCR, flow cytometry and functional analysis of tumor infiltrating lymphocytes. A subset of CRC displayed high infiltration with activated CD8+ CTL as well as activated Th1 cells characterized by IFN-γ 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 up-regulated 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 CRC.
Subfields: Oncology, Pathology and Forensic Medicine
View Paper: https://www.semanticscholar.org/paper/e1a0226e298a11fa39fa147de797243d4d53c5fb
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Citations in the corpus
- PD-1 Blockade in Tumors with Mismatch-Repair Deficiency (2015, neutral): “A recent study refined these classic observations by showing that the mismatch repair–deficient tumor microenvironment strongly expressed several immune checkpoint ligands, including PD-1, PDL1, CTLA-4, LAG-3, and IDO, which indicates that their active immune microenvironment is counterbalanced by i”
- The clinical role of the TME in solid cancer (2018, positive): “Furthermore, MSI CRC tumours display increased infiltration with CD8 T cells, B cells and macrophages, as well as an increased expression of Th1related genes.(19,20) Second, some driver or passenger mutations can induce molecular pathways that shape tumour infiltration by immune cells independently ”