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Immune Landscape Refines the Classification of Colorectal Cancer With Heterogeneous Prognosis, Tumor Microenvironment and Distinct Sensitivity to Frontline Therapies.

ABSTRACT: The immune microenvironment has profound impacts on the initiation and progression of colorectal cancer (CRC). Therefore, the goal of this article is to identify two robust immune subtypes in CRC, further provide novel insights for the underlying mechanisms and clinical management. In this study, two CRC immune subtypes were identified using the consensus clustering of immune-related gene expression profiles in the meta-GEO dataset (n = 1,198), and their reproducibility was further verified in the TCGA-CRC dataset (n = 638). Subsequently, we characterized the immune escape mechanisms, gene alterations, and clinical features of two immune subtypes. Cluster 1 (C1) was defined as the "immune cold subtype" with immune cell depletion and deficiency, while cluster 2 (C2) was designed as the "immune hot subtype", with abundant immune cell infiltration and matrix activation. We also underlined the potential immune escape mechanisms: lack of MHC molecules and defective tumor antigen presentation capacity in C1, increased immunosuppressive molecules in C2. The prognosis and sensitivity to 5-FU, Cisplatin and immunotherapy differed between two subtypes. According to the two immune subtypes, we developed a prognosis associated risk score (PARS) with the accurate performance for predicting the prognosis. Additionally, two nomograms for overall survival (OS) and disease-free survival (DFS) were further constructed to facilitate clinical management. Overall, our research provides new references and insights for understanding and refining the CRC.

SUBMITTER: Liu Z

PROVIDER: S-EPMC8784608 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Clear cell renal cell carcinoma (ccRCC) is an aggressive urological cancer that originates from the proximal tubular epithelium. As one of the most common post-translational modification, protein arginine methylation plays a pivotal role in various cancer-associated biological functions, especially in cancer immunity. Therefore, constructing a protein arginine methylation-related prognostic signature would be beneficial in guiding better personalized clinical management for patients with ccRCC. Methods: Based on the multi-omics profiling of the expression levels of eight protein arginine methyltransferases (PRMTs) in 763 ccRCC samples (from TCGA, CPTAC, EMBL, and ICGC databases), we established a scoring system with machine-learning algorithms to quantify the modification patterns on clinical and immunological characterizations of individual ccRCC patient, which was termed as PRMTScore. Moreover, we utilized two external clinical cohorts receiving immunotherapy (n=302) to validate the reliability of the PRMTScore system. Multiplex immunohistochemistry (mIHC) was performed to characterize the cellular composition of 30 paired ccRCC samples. The proteomic profiling of 232 ccRCC samples obtained from Fudan University Shanghai Cancer Center (FUSCC) was analyzed to validate the protein expression of PRMT5 in ccRCC. Finally, CCK-8, transwell, and wound healing assays were conducted to elucidate the role of PRMT5 in ccRCC in vitro. Results: A total of 763 ccRCC patients with available multi-omics profiling were stratified into two clusters (PRMTCluster A and B) with distinctive prognosis, genomic alterations, tumor microenvironment (TME) characteristics, and fundamental biological mechanisms. Subsequently, protein arginine methylation-related prognostic signature (PRMTScore) was constructed and consisted of SLC16A12, HRH2, F2RL3, and SAA1. The PRMTScore showed remarkable differences in outcomes, immune and stromal fractions, expressions of immune checkpoints, the abundance of immune cells, and immunotherapy response in ccRCC patients. Additionally, preliminary insights unveiled the tumor-suppressive role of PRMT5 in ccRCC, and the signal of PRMT5low significantly predicted aggressive prognosis and the high abundance of PD1+ CD8+ cells in ccRCC. Conclusion: We constructed a PRMTScore system, which showed the potent ability to assess the prognosis, TME characteristics, and immunotherapy response for patients with ccRCC. Moreover, this is the first study to propose that PRMT5 acts as a cancer suppressor in ccRCC.

Project description:Background: Recent studies have found that senescence-associated genes play a significant role in cancer biological processes. We aimed to analyze the characteristics and role of senescence-associated genes in triple-negative breast cancer (TNBC). Methods: We systematically screened senescence-associated secretory phenotype (SASP) genes based on the gene expression information in the TCGA database. According to the expression levels of senescence-associated genes, TNBC was classified into two subtypes, namely, TNBCSASP1 and TNBCSASP2, using an unsupervised cluster algorithm. We then performed gene expression, enrichment pathway, immune infiltration, mutational profile characterization, drug sensitivity and prognostic value analyses for the two subtypes. The reliability and prognostic predictive utility of this classification model were validated. The most prognostically relevant gene, FAM3B, was comprehensively identified and validated by tissue microarray in TNBC. Results: TNBC was classified into two senescence-associated subtypes, TNBCSASP1 and TNBCSASP2, based on the set of senescence-associated secretory phenotype genes, among which the TNBCSASP1 subtype had a poor prognosis. The TNBCSASP1 subtype was immunosuppressed, with suppressed immune-related signaling pathways and low immune cell infiltration. The effect of the mutation on the TP53 and TGF-β pathways could be related to the poor prognosis of the TNBCSASP1 subtype. Drug sensitivity analysis showed that AMG.706, CCT007093, and CHIR.99021 were potential targeted drugs for the TNBCSASP1 subtype. Finally, FAM3B was a key biomarker affecting the prognosis of patients with triple-negative breast cancer. Compared to normal breast tissue, the expression of FAM3B was reduced in triple-negative breast cancer. Survival analysis showed that overall survival was significantly shorter in triple-negative breast cancer patients with high FAM3B expression. Conclusion: A senescence-associated signature with different modification patterns has critical potential for providing a better understanding of TNBC biological processes, and FAM3B might serve as an applicable target for TNBC therapy.

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Immune Landscape Refines the Classification of Colorectal Cancer With Heterogeneous Prognosis, Tumor Microenvironment and Distinct Sensitivity to Frontline Therapies.

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