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 PERLowTIM3High 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 PERLowTIM3High 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 PERLowTIM3High 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.

Cell Type-Specific Induction of Inflammation-Associated Genes in Crohn’s Disease and Colorectal Cancer

“…Similarly, the induction of HLA-C, which we have shown in all of these populations, can be explained via induction by TNFα [ 39 ]. The importance of these expression patterns is highlighted by the application of TNFα inhibitors as a mainstay therapy for over 20 years [ 40 , 41 , 42 ].…”

Altered expression of ACOX2 in non-small cell lung cancer

“…In this regard, in LUAD a negative correlation between ACOX2 expression and CD8 + T cell infiltration (Table 4 a) occurs, whereas in LUSC a positive correlation between ACOX2 expression and CD8 + T cell infiltration is observed (Table 4 a). As such it is possible that this observation may have potential implications for patient management for checkpoint inhibitors given that CD8 + tumour infiltrating lymphocytes are associated with better outcome in NSCLC [ 82 , 83 ]. Moreover, in colon adenocarcinomas, reduced peroxisomal number and associated enzymatic activities occurs, and most recently an at-risk subpopulation has been identified where a low peroxisome pathway score is associated with a worse clinical outcome and high immune cell infiltration in CRC patients [ 84 ], and suggesting that peroxisomal genes such as ACOX2 could potentially be used in a similar fashion to explore for further associations with respect to utility in a predictive score for checkpoint inhibitor stratification or outcome in NSCLC.…”

Case report: Complete pathologic response with first-line immunotherapy combination in a young adult with massive liver dissemination of mismatch repair–deficient metastatic colorectal cancer: Immunological and molecular profiling

“…Similarly, the slight expression of PD-L1 in PT can be considered another favorable prognostic feature, although still debated ( 27 – 29 ). Despite the role of LAG-3 and TIM-3 is still open to discussion ( 30 – 34 ), these molecules may not be considered as independent and isolated immune inhibitors but rather as co-indicators together with PD-1 of a still active inflammatory response where T cells are activated to exert their antitumor activity, and a part of them is progressively turning off and becoming exhausted. Therefore, the co-expression of PD-1, LAG-3, and TIM-3 on T cells suggests that additional combinatory immune checkpoint blockade therapies could be required in poorly responding cases ( 35 , 36 ).…”