Correlation between <i>CARINH</i> expression and clinical outcomes in metastatic clear-cell renal cell carcinoma (mccRCC).

Abstract

4553 Background: CARINH is an interferon (IFN)-responsive long non-coding RNA that promotes IRF1 expression and downstream IFN signaling. Higher CARINH expression improves outcomes in esophageal cancer through suppressed tumor growth (Huang et al, 2019). Despite the immunogenic nature of RCC, the role of CARINH in its immunogenicity remains unexplored. Here, we examine the role of CARINH in predicting progression in mccRCC patients (pts) treated with systemic therapy. Methods: We included pts with RNA-seq data from 2 first-line clinical trials in mccRCC: Javelin Renal-101 (JR; n = 741) and CheckMate9ER (CM9; n = 403). Transcripts per million (TPM) were log2-transformed and scaled per 1 SD change. IMmotion150 T eff and Myeloid signatures, and tumor inflammatory score (TIS) were computed as means of their log2-transformed genes’ TPMs then scaled. Multivariable (MV) Cox models assessed progression-free survival (PFS) per increase in CARINH expression and compared PFS for each immune signature with and without CARINH expression, using likelihood ratio test (LRT). Log-rank test compared PFS between high and low CARINH expression groups with median split. Spearman correlation associated CARINH expression and immune signatures. MV logistic regression estimated progression odds ratio between pts who progressed (RECIST 1.1: PD), and those who didn’t (CR, PR, SD and NCR/NPD). MV analyses adjusted (adj) for age, sex, treatment arm, IMDC risk and sarcomatoid features. Results: In MV Cox analysis, higher CARINH was associated with improved PFS in both trials (JR: HR adj = 0.87 - 95% CI: 0.79-0.96, p = 4.5×10 -3 ; CM9: HR adj = 0.82 - 95% CI: 0.73-0.93, p = 1.3×10⁻³), regardless of treatment arm (LRT p &gt; 0.05). Log-rank test, comparing high and low expression groups, revealed longer PFS with high expression in every cohort and their arms (p &lt; 0.05), except for sunitinib in CM9 (p = 0.18). Higher CARINH expression correlated positively with T eff and TIS signatures (ρ = 0.51-0.54) and negatively with Myeloid signature (ρ = −0.14 to −0.10) in both trials (p &lt; 0.05). CARINH expression improved PFS prediction over immune signatures in both trials (Table). Higher expression was associated with lower progression odds (JR: OR adj = 0.74 - 95% CI: 0.60–0.91, p = 3.7×10⁻³; CM9: OR adj = 0.68 - 95% CI: 0.47–0.98, p = 0.04), independent of arm (LRT p &gt; 0.05). Conclusions: In mccRCC, higher CARINH expression associates with lower progression odds and improved PFS beyond that predicted by immune signatures. Translational efforts to characterize its role in mccRCC pathophysiology and clinical outcomes are ongoing. MV Cox for PFS prediction by immune signature after adding CARINH expression. Trial Immune Signature HR adj (with CARINH) 95% CI LRT FDR-adj p-value JR TIS 0.86 0.76-0.97 0.02 JR T eff 0.88 0.79-0.99 0.04 JR Myeloid 0.87 0.80-0.96 0.02 CM9 TIS 0.84 0.72-0.97 0.02 CM9 T eff 0.81 0.70-0.94 7.2×10⁻³ CM9 Myeloid 0.82 0.73-0.93 4.6×10⁻³