Hot clear cell renal cell carcinoma immune status: Illusion or reality?

Abstract

e16575 Background: High tumor mutation burden (TMB) and increased CD8+ T cells infiltration are associated with positive ICIs response in many solid cancers. But non-responsive clear cell renal cell carcinoma (ccRCC) features modest TMB, high CD8+ T-cell infiltration but poor survival. Costimulatory molecules confer immune cell activation within the immune response. Therefore, we aimed to investigate ccRCC’s unique immune environment related prognosis and ICIs’ sensitivity from the aspect of co-stimulation alteration. Methods: We analyzed the combined ccRCC cohort of 844 patients’ RNA sequencing data, from two sources: One ccRCC group (533 patients) was from The Cancer Genome Atlas KIRC (TCGA-KIRC), and the validation group (311 patients) was from an ICIs treated clinical trial. Univariate, LASSO, and multivariate Cox regression analyses were used to identify overall survival-related costimulatory genes, which were used to build an immune prognostic model (IPM) stratifying survival risk level in ccRCC. Comprehensive bioinformatics discovered the relationship between immune status, ICIs’ sensitivity with IPM’ prognosis risk. Results: The survival related co-stimulatory genes were identified in 533 ccRCC patients to construct an immune prognostic model (IPM) to differentiate patients with a low or high risk of poor survival (AUC = 0.75). Functional enrichment analysis showed T cell homeostasis represented the major function alteration related to IPM risk score ( P< 0.05). ICIs clinical trial cohort validated the IPM’s moderate prediction performance for the ICIs response ( P= 0.028), for IPM-high risk patients are more likely to be resistant to ICIs. The high-risk group had higher CD8 + T cell infiltration, higher TMB, and higher cytolytic activity, while such a hot immune status was an illusion concealing the T cells homeostasis alteration with the increased proportion of dysfunctional CD8+ and CD4+ T cells, immunosuppressive cells (i.e., iT-regs, nT-regs, and CAFs) in IPM-high risk, this kind of refractory ccRCC subtype. Conclusions: Baseline CD8 + T cell infiltration, TMB, and cytolytic activity could not predict response to ICI in the ccRCCs, and hot tumor immune status represented by CD8+T cells in resistant ccRCC is an illusion concealing T cells homeostasis alteration. T cells homeostasis could provide critical insights into immunogenomic mechanisms contributing to the immunotherapy sensitivity in ccRCC. Our five-gene based IPM tested easily by PCR, was clinically accessible, cheap and useful for indicating refractory ccRCCs to undergo ICIs.