Gene set enrichment analysis identifies immune subtypes of kidney renal clear cell carcinoma with significantly different molecular and clinical properties.

Background: Kidney renal clear cell carcinoma (KIRC) is the most prevalent renal malignancy, marked by a high abundance of tumor-infiltrating lymphocytes (TILs) and an unfavorable prognosis upon metastasis. Numerous studies have demonstrated that KIRC possesses a tumor microenvironment that is highly heterogeneous, and this is associated with significant variations in the effectiveness of most first-line drugs administered to KIRC patients. Therefore, it is crucial to classify KIRC based on the tumor microenvironment, although these subtyping techniques are still inadequate. Methods: By applying gene set enrichment scores of 28 immune signatures, we conducted a hierarchical clustering of KIRC and determined its immune subtypes. In addition, we conducted a comprehensive exploration of the molecular and clinical features of these subtypes, including survival prognosis, proliferation, stemness, angiogenesis, tumor microenvironment, genome instability, intratumor heterogeneity, and pathway enrichment. Results: Through cluster analysis, two immune subtypes of KIRC were identified and termed Immunity-High (Immunity-H) and Immunity-Low (Immunity-L). This clustering outcome was consistent in four independent KIRC cohorts. The subtype Immunity-H exhibited elevated levels of TILs, tumor aneuploidy, homologous recombination deficiency, stemness, and proliferation potential, along with a poorer prognosis for survival. Despite this, the Immunity-L subtype demonstrated elevated intratumor heterogeneity and a stronger angiogenesis signature in contrast to Immunity-H. According to the results of pathway enrichment analysis, the Immunity-H subtype was found to be highly enriched in immunological, oncogenic, and metabolic pathways, whereas the Immunity-L subtype was highly enriched in angiogenic, neuroactive ligand-receptor interaction, and PPAR pathways. Conclusions: Based on the enrichment of immune signatures in the tumor microenvironment, KIRC can be categorized into two immune subtypes. The two subtypes demonstrate considerably distinct molecular and clinical features. In KIRC, an increase in immune infiltration is linked to a poor prognosis. Patients with Immunity-H KIRC may exhibit active responses to PPAR and immune checkpoint inhibitors, whereas patients with Immunity-L may manifest favorable responses to anti-angiogenic agents and immune checkpoint inhibitors. The immunological classification provides molecular insights into KIRC immunity, as well as clinical implications for the management of this disease.