Abstract
Despite dramatic responses to immune checkpoint inhibitors (ICIs) in patients with colon cancer (CC) harboring deficient mismatch repair (dMMR), more than half of these patients ultimately progress and experience primary or secondary drug resistance. There is no useful biomarker that is currently validated to accurately predict this resistance or stratify patients who may benefit from ICI-based immunotherapy. As hypoxic and acidic tumor microenvironment would greatly impair tumor-suppressing functions of tumor-infiltrating lymphocytes (TILs), we sought to explore distinct immunological phenotypes by analysis of the intratumoral hypoxia state using a well-established gene signature. Based on the Gene Expression Omnibus (GEO) (n = 88) and The Cancer Genome Atlas (TCGA) (n = 49) databases of patients with CC, we found that dMMR CC patients could be separated into normoxia subgroup (NS) and hypoxia subgroup (HS) with different levels of expression of hypoxia-related genes (lower in NS group and higher in HS group) using NMF package. Tumoral parenchyma in the HS group had a relatively lower level of immune cell infiltration, particularly CD8+ T cells and M1 macrophages than the NS group, and coincided with higher expression of immune checkpoint molecules and C-X-C motif chemokines, which might be associated with ICI resistance and prognosis. Furthermore, three genes, namely, MT1E, MT2A, and MAFF, were identified to be differentially expressed between NS and HS groups in both GEO and TCGA cohorts. Based on these genes, a prognostic model with stable and valuable predicting ability has been built for clinical application. In conclusion, the varying tumor-immune microenvironment (TIME) classified by hypoxia-related genes might be closely associated with different therapeutic responses of ICIs and prognosis of dMMR CC patients.
Highlights
Colon cancer (CC) is the most prevalent type of malignancy worldwide, resulting in the fifth leading cause of death in 2020 [1]. e standard therapeutic procedures for advancedCC are surgery plus adjuvant therapy or neoadjuvant therapy
We used univariate Cox analysis to identify the prognostic value of hypoxia-related genes. en, genes with p < 0.05 were chosen for subsequent analysis. e combined gene set, which contained 88 deficient mismatch repair (dMMR) CC patients, was clustered using an unsupervised nonnegative matrix factorization (NMF) package [20]. e optimal clustering number was chosen according to the k value when the cophenetic correlation coefficient started to decline. en, the clustering result was evaluated using principal component analysis (PCA) and t-distributed stochastic neighbor embedding (t-SNE)
We filtered 22 genes that were associated with the prognosis of dMMR patients from the 200 hypoxiarelated gene list obtained from the Gene Set Enrichment Analysis (GSEA) database (Table S2)
Summary
Colon cancer (CC) is the most prevalent type of malignancy worldwide, resulting in the fifth leading cause of death in 2020 [1]. e standard therapeutic procedures for advanced. Some studies reported that higher level of TMB and large production of neoantigens were closely associated with the infiltration of immune cells and the response rate to immunotherapy [8], whereas many factors, such as restrained oxygen and nutrients, may impact tumor-infiltrating lymphocytes (TILs), leading to diverse and complex TME [9, 10]. The increased expression of lactic acid, which is the typical feature of hypoxia TME, plays an important immunosuppressive role by restraining the metabolism of TILs and inhibits the production of interferon-c (IFN-c) [14, 15]. We have developed a prognostic model for dMMR CC patients in clinical application
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