The Balance Between Cytotoxic T-cell Lymphocytes and Immune Checkpoint Expression in the Prognosis of Colon Tumors

J Natl Cancer Inst. 2018 Jan 1;110(1). doi: 10.1093/jnci/djx136.

Abstract

Background: Immune checkpoint (ICK) expression might represent a surrogate measure of tumor-infiltrating T cell (CTL) exhaustion and therefore be a more accurate prognostic biomarker for colorectal cancer (CRC) patients than CTL enumeration as measured by the Immunoscore.

Methods: The expression of ICKs, Th1, CTLs, cytotoxicity-related genes, and metagenes, including Immunoscore-like metagenes, were evaluated in three independent cohorts of CRC samples (260 microsatellite instable [MSI], 971 non-MSI). Their associations with patient survival were analyzed by Cox models, taking into account the microsatellite instability (MSI) status and affiliation with various Consensus Molecular Subgroups (CMS). PD-L1 and CD8 expression were examined on a subset of tumors with immunohistochemistry. All statistical tests were two-sided.

Results: The expression of Immunoscore-like metagenes was statistically significantly associated with improved outcome in non-MSI tumors displaying low levels of both CTLs and immune checkpoints (ICKs; CMS2 and CMS3; hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.43 to 0.92, P = .02; and HR = 0.55, 95% CI = 0.34 to 0.90, P = .02, respectively), but clearly had no prognostic relevance in CRCs displaying higher levels of CTLs and ICKs (CMS1 and CMS4; HR = 0.46, 95% CI = 0.10 to 2.10, P = .32; and HR = 1.13, 95% CI = 0.79 to 1.63, P = .50, respectively), including MSI tumors. ICK metagene expression was statistically significantly associated with worse prognosis independent of tumor staging in MSI tumors (HR = 3.46, 95% CI = 1.41 to 8.49, P = .007). ICK expression had a negative impact on the proliferation of infiltrating CD8 T cells in MSI neoplasms (median = 0.56 in ICK low vs median = 0.34 in ICK high, P = .004).

Conclusions: ICK expression cancels the prognostic relevance of CTLs in highly immunogenic colon tumors and predicts a poor outcome in MSI CRC patients.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / genetics
  • B7-H1 Antigen / analysis
  • B7-H1 Antigen / genetics
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / immunology*
  • CD8 Antigens / analysis
  • CTLA-4 Antigen / genetics
  • Colon / chemistry
  • Colorectal Neoplasms / chemistry
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / immunology*
  • Colorectal Neoplasms / pathology
  • Female
  • Gene Expression
  • Hepatitis A Virus Cellular Receptor 2 / genetics
  • Humans
  • Inducible T-Cell Co-Stimulator Protein / genetics
  • Lymphocyte Activation Gene 3 Protein
  • Lymphocytes, Tumor-Infiltrating*
  • Male
  • Microsatellite Instability
  • Middle Aged
  • Neoplasm Staging
  • Prognosis
  • Programmed Cell Death 1 Ligand 2 Protein / genetics
  • Programmed Cell Death 1 Receptor / genetics
  • Retrospective Studies
  • Survival Rate
  • T-Lymphocytes, Cytotoxic*
  • Th1 Cells

Substances

  • Antigens, CD
  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human
  • CD8 Antigens
  • CTLA-4 Antigen
  • HAVCR2 protein, human
  • Hepatitis A Virus Cellular Receptor 2
  • ICOS protein, human
  • Inducible T-Cell Co-Stimulator Protein
  • PDCD1 protein, human
  • PDCD1LG2 protein, human
  • Programmed Cell Death 1 Ligand 2 Protein
  • Programmed Cell Death 1 Receptor
  • Lymphocyte Activation Gene 3 Protein
  • Lag3 protein, human