Analysis of immune‑related signatures of colorectal cancer identifying two different immune phenotypes: Evidence for immune checkpoint inhibitor therapy

Abstract

Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of numerous types of cancer, including colorectal cancer (CRC). Patients with CRC and deficient mismatch repair or high microsatellite instability could benefit from ICI treatment, although the response rate of most patients is low. Therefore, the immune subtyping of patients with CRC is required in order to determine the subtypes suitable for ICI treatment. The present study used a cohort of patients with CRC from The Cancer Genome Atlas (TCGA) to perform molecular subtyping, with results validated in three CRC cohorts from the Gene Expression Omnibus. Non-negative matrix factorization was used to achieve consensus molecular subtyping. The tumor immune dysfunction and exclusion algorithm was used to predict potential ICI therapy responses and gene set enrichment analysis was performed to define different pathways associated with the immune response. Two distinct subtypes of CRC were finally identified in TCGA cohorts, which were characterized as significantly different prognostic subtypes (low-risk and high-risk subtypes). Higher expression of programmed death-ligand 1, higher proportion of tumor-infiltrating lymphocytes and tumor mutation burden were significantly enriched in the low-risk subtype. Further pathway analysis revealed that the low-risk subtype was associated with immune response activation and signaling pathways involved in 'antigen processing and presentation'. Three independent CRC cohorts were used to validate the above findings. In summary, two clinical CRC subtypes were identified, which are characterized by significantly different survival outcomes and immune infiltration patterns. The findings of the present study suggest that ICI treatment may be more effective in the low-risk CRC subtype.

Gene expression and DNA methylation analyses suggest that two immune related genes are prognostic factors of colorectal cancer

“…Cancer immunotherapy has demonstrated promising advantages in the treatment efficiency and long-term survival of cancer patients [ 25 ]. For example, Chen et al reported that CRC patients with different subtypes exhibit different survival outcomes and immune infiltration patterns [ 26 ]. Immune checkpoint inhibitor therapy is more effective in low-risk CRC subtypes.…”

Tumor-Infiltrating Lymphoid Cells in Colorectal Cancer Patients with Varying Disease Stages and Microsatellite Instability-High/Stable Tumors

“…Kitsou et al, have recently reported associations between elevated PD-1 and TIGIT gene expression with better overall survival, and reported associations between TIL load and HAVCR2 , LAG -3 and TIGIT in CRC patients [ 11 ]. Chen et al also reported elevated expression of PD-L1, TIL load and mutation burden in low-risk CRC patients [ 47 ]. Importantly, the consensus molecular subtypes (CMS) classified CRC subtypes into four groups based on genetic modifications and tumor immune profiling; CMS1 (MSI-H, immune activated), CMS2 (activated WNT and MYC signaling), CMS3 (dysregulation of metabolic pathways) and CMS4 (immune inflamed, TGF-β activation) [ 48 ].…”

AURKA and FAM83A are prognostic biomarkers and correlated with Tumor-infiltrating Lymphocytes in smoking related Lung Adenocarcinoma

“…It is important that TILs are related to prognosis of several cancers, including colorectal cancer 41 , ovarian cancer 42 , breast cancer 43 as well as lung cancer 44 . Besides, the significance of TILs on the prognosis of many cancer types has been examined.…”