Fusion-driven oncogenic programs shape the immune landscape in translocation renal cell carcinoma

Area of Science:

• Oncology
• Genetics
• Immunology

Background:

• Renal cell carcinomas (RCCs) are molecularly diverse but often treated empirically due to poor understanding of subtype-specific biology.
• Clear cell RCC (ccRCC) is the most common subtype, and current therapies are primarily designed for it.
• Translocation RCC (tRCC), defined by TFE3 gene fusions, is an aggressive subtype with unclear biological drivers.

Purpose of the Study:

• To investigate the distinct molecular and cellular features of translocation renal cell carcinoma (tRCC).
• To understand the oncogenic programs and tumor microenvironment (TME) specific to tRCC.
• To identify potential therapeutic strategies based on tRCC-specific biology.

Main Methods:

• Analysis of single-cell transcriptomes from tRCC tumors.
• Chromatin accessibility profiling of tRCC.
• Comparative analysis with ccRCC to identify subtype-specific differences.

Main Results:

• tRCCs exhibit distinct oncogenic programs and a markedly immunosuppressive TME, despite a similar cell of origin as ccRCC.
• Six conserved tumor meta-programs were identified in tRCC, including epithelial-mesenchymal transition (EMT) and proximal tubule identity programs.
• TFE3 fusion activity regulates the balance of these programs, driving an EMT program associated with exhausted CD8+ T cells, SPP1+ macrophages, and matrix-associated fibroblasts (mCAFs).

Conclusions:

• tRCC possesses unique TFE3 fusion-driven biology that differs significantly from ccRCC.
• The identified oncogenic programs and immunosuppressive TME in tRCC explain its reduced responsiveness to immunotherapy compared to ccRCC.
• Targeting fusion-driven oncogenic programs and reprogramming the tRCC TME are potential therapeutic avenues.