KRAS Mutation and Consensus Molecular Subtypes 2 and 3 Are Independently Associated with Reduced Immune Infiltration and Reactivity in Colorectal Cancer

Abstract

mutation is a common canonical mutation in colorectal cancer, found at differing frequencies in all consensus molecular subtypes (CMS). The independent immunobiological impacts of RAS mutation and CMS are unknown. Thus, we explored the immunobiological effects of mutation across the CMS spectrum. Expression analysis of immune genes/signatures was performed using The Cancer Genome Atlas (TCGA) RNA-seq and the KFSYSCC microarray datasets. Multivariate analysis included status, CMS, tumor location, MSI status, and neoantigen load. Protein expression of STAT1, HLA-class II, and CXCL10 was analyzed by digital IHC. The Th1-centric co-ordinate immune response cluster (CIRC) was significantly, albeit modestly, reduced in -mutant colorectal cancer in both datasets. Cytotoxic T cells, neutrophils, and the IFNγ pathway were suppressed in-mutant samples. The expressions of STAT1 and CXCL10 were reduced at the mRNA and protein levels. In multivariate analysis, mutation, CMS2, and CMS3 were independently predictive of reduced CIRC expression. Immune response was heterogeneous across-mutant colorectal cancer: -mutant CMS2 samples have the lowest CIRC expression, reduced expression of the IFNγ pathway, and , and reduced infiltration of cytotoxic cells and neutrophils relative to CMS1 and CMS4 and to wild-type CMS2 samples in the TCGA. These trends held in the KFSYSCC dataset. mutation is associated with suppressed Th1/cytotoxic immunity in colorectal cancer, the extent of the effect being modulated by CMS subtype. These results add a novel immunobiological dimension to the biological heterogeneity of colorectal cancer. .

Kras mutation correlating with circulating regulatory T cells predicts the prognosis of advanced pancreatic cancer patients

“…These cells in turn promote and maintain tumor growth and metastasis. Several studies identified that Kras G12D or Kras G12V mutation contributes to T cell differentiation in colorectal and lung cancer cells . Our previous studies also found that Kras G12D mutation is associated with high Tregs infiltration in resectable pancreatic cancer tissues .…”

“…Several studies identified that Kras G12D or Kras G12V mutation contributes to T cell differentiation in colorectal and lung cancer cells. 13,31 Our previous studies also found that Kras G12D mutation is associated with high Tregs infiltration in resectable pancreatic cancer tissues. 14 However, the potential correlation of Kras mutation and T cell subsets is still unclear in advanced pancreatic cancer.…”

Gene-Specific Methylation Profiles for Integrative Methylation-Expression Analysis in Cancer Research

“…CMS4 patients have poorer prognosis and perhaps need more aggressive treatment, and they show limited benefit from Oxaliplatin (Song et al 2016;Okita et al 2018). Patients with CMS2 or CMS3 may benefit from addition of Bevacizumab (Mooi et al 2018) but are not good candidates for immunotherapy (Becht et al 2016;Lal et al 2018), and anti-EGFR therapy appears to work very well for CMS2 patients but not CMS1 (Okita et al 2018).…”

Mechanisms of immunogenicity in colorectal cancer

“…About 20 per cent of patients in the MSS colorectal cancer subgroup develop an immunogenomic signature similar to that in MSI‐H colorectal cancer, despite low mutational burden. There is evidence that activating mutations in the Ras–MAPK pathway are associated with lower expression of this immune gene cluster and immune pathway downregulation. In addition, lymphocytic infiltration, particularly of effector and memory T cells into the tumour, a key indicator of prognosis in colorectal cancer, appears to be independent of MSI status.…”