The correlation between immune subtypes and consensus molecular subtypes in colorectal cancer identifies novel tumour microenvironment profiles, with prognostic and therapeutic implications

Eur J Cancer. 2019 Dec;123:118-129. doi: 10.1016/j.ejca.2019.09.008. Epub 2019 Nov 1.


Background: Solid tumour growth is the consequence of a complex interplay between cancer cells and their microenvironment. Recently, a new global transcriptomic immune classification of solid tumours has identified six immune subtypes (ISs) (C1-C6). Our aim was to specifically characterise ISs in colorectal cancer (CRC) and assess their interplay with the consensus molecular subtypes (CMSs).

Methods: Clinical and molecular information, including CMSs and ISs, were obtained from The Cancer Genome Atlas (TCGA) (N = 625). Immune cell populations, differential gene expression and gene set enrichment analysis were performed to characterise ISs in the global CRC population by using CMSs.

Results: Only 5 ISs were identified in CRC, predominantly C1 wound healing (77%) and C2 IFN-γ dominant (17%). CMS1 showed the highest proportion of C2 (53%), whereas C1 was particularly dominant in CMS2 (91%). CMS3 had the highest representation of C3 inflammatory (7%) and C4 lymphocyte depleted ISs (4%), whereas all C6 TGF-β dominant cases belonged to CMS4 (2.3%). Prognostic relevance of ISs in CRC substantially differed from that reported for the global TCGA, and ISs had a greater ability to stratify the prognosis of CRC patients than CMS classification. C2 had higher densities of CD8, CD4 activated, follicular helper T cells, regulatory T cells and neutrophils and the highest M1/M2 polarisation. C2 had a heightened activation of pathways related to the immune system, apoptosis and DNA repair, mTOR signalling and oxidative phosphorylation, whereas C1 was more dependent of metabolic pathways.

Conclusions: The correlation of IS and CMS allows a more precise categorisation of patients with relevant clinical and biological implications, which may be valuable tools to improve tailored therapeutic interventions in CRC patients.

Keywords: Colorectal cancer; Consensus molecular subtypes; Immune subtypes; Immunotherapy; Tumour microenviroment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / classification*
  • Adenocarcinoma / genetics
  • Adenocarcinoma / immunology
  • Adenocarcinoma / metabolism
  • Adenocarcinoma, Mucinous / classification*
  • Adenocarcinoma, Mucinous / genetics
  • Adenocarcinoma, Mucinous / immunology
  • Adenocarcinoma, Mucinous / metabolism
  • Aged
  • CD8-Positive T-Lymphocytes
  • Cell Proliferation / genetics
  • Colorectal Neoplasms / classification*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / metabolism
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Genes, MHC Class I / genetics
  • Humans
  • Inflammation / immunology
  • Interferon-gamma / immunology
  • Lymphocytes / immunology
  • Lymphocytes / metabolism
  • Macrophages / immunology
  • Male
  • Microsatellite Instability
  • Monocytes / immunology
  • Monocytes / metabolism
  • Neovascularization, Pathologic
  • Prognosis
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Receptors, Antigen, T-Cell / genetics
  • Signal Transduction
  • Th1 Cells / immunology
  • Th17 Cells / immunology
  • Th2 Cells / immunology
  • Transforming Growth Factor beta / immunology
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology
  • Wnt Signaling Pathway / genetics
  • Wound Healing / genetics
  • Wound Healing / immunology


  • KRAS protein, human
  • Proto-Oncogene Proteins c-myc
  • Receptors, Antigen, T-Cell
  • Transforming Growth Factor beta
  • Interferon-gamma
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins p21(ras)