233P - The crosstalk between PBRM1 loss and tumor immune microenvironment (TIME) of clear cell renal cell carcinoma (ccRCC): A possible interconnection to immunotherapy response

Background

Protein polybromo-1 (PB1) encoded by the PBRM1 gene is involved in chromatin-remodeling processes as a part of the SWI/SNF complex. Pathogenic variants of PBRM1 gene are commonly encountered in ccRCC. Much attention has been drawn to the predictive potential of PBRM1 to immunotherapeutic agents’ response in solid tumors. This work aims to establish an interconnection between PBRM1 loss and TIME of ccRCC.

Methods

The ccRCC cohort was obtained from the Cancer Genome Atlas Program (TCGA). Patients were stratified based on the presence of PBRM1 pathological variants into wild type group (n = 213) or mutant group (n = 153). TIME was evaluated through the enrichment of immunological processes-related gene sets using gene set enrichment analysis (GSEA) within the hallmarks of cancer and ontology gene sets. A gene set was considered significantly enriched with a P-value < .05 and a false discovery rate (FDR) ≤ 0.25. Immune cells infiltration was explored using precalculated infiltration scores of xCell. T-cell dysfunction score was obtained from TIDE server.

Results

GSEA illustrated enrichments in three immunological sets within the hallmarks of cancer, including TNF-α signaling through NF-κB (enrichment score (ES) = 0.43, Q value < .001, FDR = 0.007), INF-α response (ES = 0.34, Q value = .03, FDR = 0.190), and INF-γ response (ES = 0.39, Q value < .001, FDR = 0.022). Gene ontology sets screening highlighted the effect of PBRM1 loss on CXCR chemokine receptor binding (ES = 0.75, Q value < .001, FDR = 0.202) with no enriched sets within the cellular component or biological process sections. The mutant group showed a significant CD8+ T-cells depletion alongside reduced infiltration of eosinophils, cancer-associated fibroblasts, M1 macrophages, and T helper 2 cells. PBRM1 damage did not induce a T-cell dysfunction (z score = 0.726, P = .468). In addition, PBRM1 loss was correlated with a superior response to nivolumab in a cohort of 35 patients (fold change = 58.7 and P = .0123).

Conclusions

PBRM1 Loss induces global transcription alternations that impact many immunological processes. Such phenomena could be associated with the positive correlation to immunotherapy response in ccRCC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.