Multi-omic characterization of 14q deletion in renal clear cell carcinoma identifies EDNRB as a predictor of immunotherapy response.
Although chromosome 14q deletion (14q-) is present in up to 40% of clear cell renal cell carcinoma (ccRCC) cases, its immunologic and molecular impact remains unclear. Because TRAF3 and NFΚBIA, key regulators of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, are located on 14q, we hypothesize that 14q- in ccRCC promotes increased inflammation and unique determinants of immune checkpoint blockade (ICB) response.
We collected data from 825 patients with ccRCC from publicly available sources, our own independent retrospective study, and the Oncology Research Information Exchange Network. These data include bulk RNA-sequencing (RNA-seq), single-cell RNA-seq (scRNA-seq), and whole exome sequencing (WES). We also include reverse phase protein array from DepMap cell lines (n=277). Next, we performed multiplex immunofluorescence for spatial analysis of immune cells on 23 patient slides with paired WES and ICB response. Finally, progression-free survival, 14q- status (assessed in bulk RNA-seq or whole exome sequencing), and kidney inflammatory marker EDNRB expression were assessed in two independent ICB immunotherapy trials.
14q- status is associated with increased NF-κB-target transcription and p65 phosphorylation. Tumor scRNA-seq revealed increased expression of CCL20, an NF-κB target and lymphotactic protein. Simultaneously, single-cell and bulk RNA-seq demonstrated higher effector CD8+T cell infiltration in 14q- tumors compared with controls. We investigated myeloid panel mIF images from 14q- tumors and found dendritic cells (DCs) significantly aggregate with tumor cells in ICB responders compared with non-responders. Cell-cell communication analysis on DCs and tumor cells from a 14q- responder revealed tumor-derived EDN1 is uniquely interacting with EDNRB on DCs. In two ICB trials, 14q- combined with elevated EDNRB expression correlated with significantly improved progression-free survival.
This is the first evidence that 14q- in ccRCC is associated with an antitumor inflammatory phenotype, possibly driven by aberrant NF-κB activation. Furthermore, 14q- with high EDNRB expression (EDNRB+) may serve as a predictive biomarker for ICB response in ccRCC. Finally, our results indicate patients with 14q-/EDNRB- may respond poorly to immunotherapy and new treatment options should be explored for this cohort.
We collected data from 825 patients with ccRCC from publicly available sources, our own independent retrospective study, and the Oncology Research Information Exchange Network. These data include bulk RNA-sequencing (RNA-seq), single-cell RNA-seq (scRNA-seq), and whole exome sequencing (WES). We also include reverse phase protein array from DepMap cell lines (n=277). Next, we performed multiplex immunofluorescence for spatial analysis of immune cells on 23 patient slides with paired WES and ICB response. Finally, progression-free survival, 14q- status (assessed in bulk RNA-seq or whole exome sequencing), and kidney inflammatory marker EDNRB expression were assessed in two independent ICB immunotherapy trials.
14q- status is associated with increased NF-κB-target transcription and p65 phosphorylation. Tumor scRNA-seq revealed increased expression of CCL20, an NF-κB target and lymphotactic protein. Simultaneously, single-cell and bulk RNA-seq demonstrated higher effector CD8+T cell infiltration in 14q- tumors compared with controls. We investigated myeloid panel mIF images from 14q- tumors and found dendritic cells (DCs) significantly aggregate with tumor cells in ICB responders compared with non-responders. Cell-cell communication analysis on DCs and tumor cells from a 14q- responder revealed tumor-derived EDN1 is uniquely interacting with EDNRB on DCs. In two ICB trials, 14q- combined with elevated EDNRB expression correlated with significantly improved progression-free survival.
This is the first evidence that 14q- in ccRCC is associated with an antitumor inflammatory phenotype, possibly driven by aberrant NF-κB activation. Furthermore, 14q- with high EDNRB expression (EDNRB+) may serve as a predictive biomarker for ICB response in ccRCC. Finally, our results indicate patients with 14q-/EDNRB- may respond poorly to immunotherapy and new treatment options should be explored for this cohort.
Authors
Vella Vella, Hoskins Hoskins, Miller Miller, Reeser Reeser, Wing Wing, Sheel Sheel, Samorodnitsky Samorodnitsky, Lenz Lenz, Collier Collier, Li Li, Chowdhury Chowdhury, Yang Yang, Parwani Parwani, Roychowdhury Roychowdhury
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