Characterization of Molecular Heterogeneity Associated With Tumor Microenvironment in Clear Cell Renal Cell Carcinoma to Aid Immunotherapy.

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A systematically investigation of the tumor microenvironment (TME) in ccRCC could contribute to help clinicians develop personalized treatment and facilitate clinical decision-making. In this study, we analyzed the immune-related subtype of ccRCC on the basis of immune-related gene expression data in The Cancer Genome Atlas (TCGA, N = 512) and E-MTAB-1980 (N = 101) dataset, respectively. As a result, two subtypes (C1 and C2) were identified by performing non-negative matrix factorization clustering. Subtype C1 was characterized by increased advance ccRCC cases and immune-related pathways. A higher immune score, stromal score, TMB value, Tumor Immune Dysfunction and Exclusion (TIDE) prediction score, and immune checkpoint genes expression level were also observed in C1. In addition, the C1 subtype might benefit from chemotherapy and immunotherapy. The patients in subtype C2 had more metabolism-related pathways, higher tumor purity, and a better prognosis. Moreover, some small molecular compounds for the treatment of ccRCC were identified between the two subtypes by using the Connectivity Map (CMap) database. Finally, we constructed and validated an immune-related (IR) score to evaluate immune modification individually. A high IR score corresponded to a favorable prognosis compared to a low IR score, while more advanced tumor stage and grade cases were enriched in the low IR score group. The two IR score groups also showed a distinct divergence among immune status, TME, and chemotherapy. The external validation dataset (E-MTAB-1980) and another immunotherapy cohort (IMvigor 210) demonstrated that patients in the high IR score group had a significantly prolonged survival time and clinical benefits compared to the low IR score group. Together, characterization of molecular heterogeneity and IR signature may help develop new insights into the TME of ccRCC and provide new strategies for personalized treatment.", "claims": [{"id": "claim-method", "statement": "The IR molecular subtype was identified by performing non-negative matrix factorization (NMF) clustering analysis in the “NMF” R package4 (Gillis, 2020).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34631713", "locator": "sections[4] \"Molecular Subtypes Identification\" paragraph 2", "quote": "The IR molecular subtype was identified by performing non-negative matrix factorization (NMF) clustering analysis in the “NMF” R package4 (Gillis, 2020)."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34631713", "locator": "sections[22] \"Data Availability Statement\" paragraph 2", "quote": "The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s."}], "state": "complete"}, {"id": "claim-target-result", "statement": "As a result, two subtypes (C1 and C2) were identified by performing non-negative matrix factorization clustering.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:34631713", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "As a result, two subtypes (C1 and C2) were identified by performing non-negative matrix factorization clustering."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": "As a result, two subtypes (C1 and C2) were identified by performing non-negative matrix factorization clustering.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:34631713"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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