Identification of an at-risk subpopulation with high immune infiltration based on the peroxisome pathway and TIM3 in colorectal cancer

Abstract

Background: Peroxisomes are pivotal metabolic organelles that exist in almost all eukaryote cells. A reduction in numbers and enzymatic activities of peroxisomes was found in colon adenocarcinomas. However, the role of peroxisomes or the peroxisome pathway in colorectal cancer (CRC) is not defined.

Methods: In the current study, a peroxisome score was calculated to indicate the activity of the peroxisome pathway using gene set variant analysis based on transcriptomic datasets. CIBERSORTx was chosen to infer enriched immune cells for tumors among subgroups. The SubMap algorithm was applied to predict its sensitivity to immunotherapy.

Results: The patients with a relatively low peroxisome score and high level of T-cell immunoglobulin and mucin domain 3 (TIM-3) presented the worse overall survival than others. Moreover, low peroxisome scores were associated with high infiltration of lymphocytes and poor prognosis in those CRC patients. Thus, a PER^LowTIM3^High CRC risk subpopulation was identified and characterized by high immune infiltration. The results also showed that CD8 T cells and macrophages highly infiltrated tumors of the PER^LowTIM3^High group, regardless of consortium molecular subtype and microsatellite instability status. This subgroup had the highest tumor mutational burden and overexpression of immune checkpoint genes. Further, the PER^LowTIM3^High group showed a higher probability of responding to programmed cell death protein-1-based immunotherapy. In addition, genes involved in peroxisomal metabolic processes in CRC were also investigated since peroxisome is a rather pleiotropic and highly metabolic organelle in cell. The results indicated that only those genes involved in fatty acid alpha oxidation could be used to stratify CRC patients as similar as peroxisome pathway genes.

Conclusions: We revealed the favorable prognostic value of the peroxisome pathway in CRC and provided a new CRC stratification based on peroxisomes and TIM3, which might be helpful for CRC diagnostics and personalized treatment.

Keywords: Colorectal cancer (CRC); Fatty acid alpha oxidation (FAAO); Gene set variant analysis (GSVA); Immunotherapy; Peroxisome; T-cell immunoglobulin and mucin domain 3 (TIM-3).