Abstract
BackgroundPeroxisomes 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.MethodsIn 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.ResultsThe 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.ConclusionsWe 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.
Highlights
Peroxisomes are pivotal metabolic organelles that exist in almost all eukaryote cells
A low peroxisome pathway score is associated with a worse clinical outcome and high immune cell infiltration in Colorectal cancer (CRC) patients The peroxisome score was calculated by Gene set variant analysis (GSVA) for CRC patients enrolled in the study and patients were categorized into either a Per-High or Per-Low group by the median of peroxisome scores
We performed gene set enrichment analysis (GSEA) on 50 hallmark gene sets in the Cancer Genome Atlas (TCGA) cohort and found lipid-associated gene sets, CHOLESTEROL_HOMEOSTASIS and BILE_ACID_METABOLISM, which were significantly enriched in the Per-High group (Fig. 1c), which was validated in the GSE39582 cohort (Additional file 2: Fig. S1a)
Summary
Peroxisomes are pivotal metabolic organelles that exist in almost all eukaryote cells. The role of peroxisomes or the peroxisome pathway in colorectal cancer (CRC) is not defined. Yin et al BMC Cancer (2022) 22:44 survival time for patients with unresectable CRCs, the efficacy of these therapies can be limited by drug resistance and side effects [2]. In the past few years, a better knowledge of the complex interactions between tumor cells and the immune system has led to the establishment of novel immunotherapies [3, 4]. One major immunotherapeutic obstacle of CRC is the immunosuppressive tumor microenvironment (TME), a highly complex and heterogenous contexture [7, 8]. For CRC tumors with pre-existing strong immune infiltration, restoring the suppressive effects of the TME on immune cells is a potential strategy to improve the efficacy of immunotherapy [9]. TME-based classifications are valuable for personalized immunotherapy in CRC
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