39Intratumoral viral transcriptomic signatures stratify immune phenotypes and clinical outcomes in renal cell carcinoma (RCC)

Abstract Background Unlike other cancer types the determinants of anti-PD-1 response in clear cell RCC are not well defined; ccRCC exhibits a low mutational burden and CD8+ T cells infiltration is associated with worse prognosis. Cytomegalovirus (CMV) and human papillomavirus (HPV) infections are postulated to modulate the anti-tumor immune responses within the tumor microenvironment. We sought to investigate the clinical and immunologic impact of CMV and HPV viral transcriptomic signatures, as defined by prior studies, in patients with RCC. Methods RNA-seq data from three RCC prospetive trials were upper-quartile normalized, log2-transformed (TPM + 1), and batch-corrected using ComBat. Transcriptomic scores for CMV (75 genes) and HPV (79 genes) were computed using geometric means (71 and 77 genes were found, respectively). CD8 immunofluorescence (IF) was performed on tumor samples. Overall survival (OS) and progression-free survival (PFS) were assessed using multivariable Cox regression, adjusting for age at therapy start, gender, IMDC risk, sarcomatoid/rhabdoid features, and number of previous lines received. Results A high intratumoral CMV transcriptomic score was significantly correlated with T-effector signature (ρ = 0.54, p = 4.8 × 10−6), IF tumor core CD8+ (ρ = 0.43, P < .001), IF tumor margin CD8+ (ρ = 0.41, P < .001), and myeloid signature (ρ = 0.40, P < .001). The CMV score was significantly higher in infiltrated versus excluded/desert tumors (P = .0079). The CMV score was associated with worse OS among patients receiving immune checkpoint blockade (ICB) (HR 4.98, P = .039). In contrast, the HPV transcriptomic score showed only a modest correlation with myeloid signature (ρ = 0.24, P = .051) and no association was found with OS nor PFS. Conclusions In metastatic RCC, a high tumor CMV transcriptomic score was associated with a paradoxical immune landscape, marked by CD8+ infiltration yet co-enriched with suppressive myeloid signatures, that predicts inferior overall survival following ICB. These viral signatures within the complex immune architecture of RCC may help understand immune responsiveness and resistance within distinct genomic and therapeutic contexts.