Prognostic and immunobiological relevance of an onco-immune signature in clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer. Despite advances in anti-angiogenic and immune checkpoint therapy, accurate prognostic markers that run on archival tissue are still lacking. In this retrospective study, we quantified twelve onco-immune genes in FFPE tumor blocks from 88 ccRCC patients using the NanoString nCounter platform. A three-gene score (RORC, TGFB1, and SOCS1) was derived in TCGA-KIRC by Cox regression and evaluated in external bulk, single-cell, and spatial datasets. The twelve panel genes were profiled in the archival FFPE tumors, and the score was computed for every patient. In TCGA-KIRC, the score was associated with worse overall survival independently of stage, grade, age, and tumor purity (HR 1.57, 95% CI 1.28–1.92, p < 0.001), and its association with tumor grade was reproduced across external cohorts. Further, high-risk tumors were inflamed but immune-exhausted, with interferon and IL-6/JAK/STAT3 up-regulation, fibroblast and macrophage enrichment, and a lower predicted checkpoint-response rate. RORC was associated with a favorable metabolic module and TGFB1 with an adverse inflammatory-myeloid module, and interpretable machine learning supported the same directions. We identified a three-gene onco-immune score from an FFPE-compatible panel that is associated with survival independently of stage, grade, and age, and marks immunologically exhausted tumors. The score could assist risk stratification and support precision medicine in ccRCC.