Microenvironment of metastatic site reveals key predictors of PD-1 blockade response in renal cell carcinoma

ABSTRACT Immune checkpoint blockade (ICB) therapies have globally improved the overall survival (OS) of patients with advanced cancers. However, the response rate to these treatments vary widely among patients, therefore exposing non-responders to immune-related adverse events, causing an urgent need of prior-treatment predictors of response to ICB. We investigated the tumor microenvironment (TME) of clear cell renal cell carcinoma (ccRCC) samples from primary and metastatic sites to identify predictive molecular and cellular markers of response to ICB. We revealed a significant discrepancy in treatment response between TME subgroups inferred from metastatic sites. The C3 cluster was enriched in non-responders and harbored a lower fractions of T-CD8 and plasma B cells, as well as a decreased expression of immunoglobulin genes. In addition we developed a highly predictive score that reflects the Tumor-Immunity Differential (TID) in TME to predict immunotherapy response (AUC=0.88, log-rank tests for PFS P < 0.0001, OS P = 0.01). In addition, among TID-related genes (YWHAE, CXCR6 and BTF3), YWHAE was validated as a robust predictive marker of immunotherapy response in independent cohorts of melanoma and lung cancers based on pre or on-treatment biopsies. These findings provide insights into efficient ICB treatment selection in clinical practice for patients with advanced cancers.