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The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints

  • Nicolas L Losa1,
  • Michael Cruise2,
  • Ada Tam1,
  • Elizabeth Wick1,
  • Elizabeth Hechenbleikner1,
  • Janis M Taube1,
  • Richard Blosser3,
  • Hongni Fan4,
  • Hao Wang4,
  • Brandon Luber4,
  • Ming Zhang4,
  • Nickolas Papadopoulos4,
  • Kenneth Kinzler4,
  • Bert Vogelstein4,
  • Cynthia Sears4,
  • Robert A Anders1,
  • Drew Pardoll1,
  • Franck Housseau4 and
  • Nicholas Siegel4
Journal for ImmunoTherapy of Cancer20153(Suppl 2):P410

Published: 4 November 2015


Colorectal CancerMismatch RepairMicrosatellite InstabilityTumor Infiltrate LymphocyteImmune Checkpoint

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-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 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. Our findings 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 CRC selectively up-regulates at least 5 checkpoint molecules that are targets of inhibitors currently being clinically tested. Furthermore, our results were clinically validated in a Phase II study at Hopkins which showed mismatch-repair status as a predictor of clinical benefit to immune checkpoint blockade with pembrolizumab.

Authors’ Affiliations

Johns Hopkins University School of Medicine, Baltimore, USA
Cleveland Clinic, Cleveland, USA
Johns Hopkins University: School of Medicine, Baltimore, USA
Johns Hopkins Hospital, Baltimore, USA


© Losa et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.