Spatial analysis reveals a novel inflammatory tumor transition state which promotes a macrophage-driven induction of sarcomatoid renal cell carcinoma

May, A. M.; Kadomoto, S.; Williams, C.; Soupir, A. C.; The, S.; McGue, J. J.; Robinson, T.; Shelley, G.; Hayes, M. T.; Fridley, B. L.; Balasi, J. A.; Ramos Echevarria, P. M.; Dhillon, J.; Nallandhighal, S.; Acharyya, S.; Chen, L.; Aldous, J.; Schurman, N.; Baladandayuthapani, V.; Frankel, T. L.; Salami, S. S.; Manley, B. J.; Mehra, R.; Udager, A. M.; Keller, E. T.

doi:10.1101/2025.06.12.656421

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bioRxiv · 10.1101/2025.06.12.656421

Spatial analysis reveals a novel inflammatory tumor transition state which promotes a macrophage-driven induction of sarcomatoid renal cell carcinoma

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Abstract

Sarcomatoid renal cell carcinoma (sRCC) is an aggressive transdifferentiation of epithelioid clear cell RCC (ccRCC) tumors that shows heightened response to immunotherapy. The underlying biology leading to sarcomatoid transformation and mechanisms contributing to immunotherapy response are not well understood. Novel single cell spatial techniques were used in ccRCC and sRCC tumors from 40 patients to understand the spatial sRCC transformation and corresponding immune changes. A transcriptional transition state in epithelioid ccRCC cells along a continuum to mesenchymal sRCC was identified which expresses high levels of pro-inflammatory cytokines and an immune infiltrate. In vitro studies demonstrated that M2-like macrophages, recruited to the tumor by the transition state, induce full transition to the sarcomatoid state. A combination of increased PD-L1 expression and T-cells recruited by the transition state was observed, consistent with the increased immunotherapy response. This study enriches our understanding of the mechanisms leading to development and immune responsiveness of sRCC paving the way for novel approaches to diminish RCC progression.

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May, A. M., Kadomoto, S., Williams, C., Soupir, A. C., The, S., McGue, J. J., Robinson, T., Shelley, G., Hayes, M. T., Fridley, B. L., Balasi, J. A., Ramos Echevarria, P. M., Dhillon, J., Nallandhighal, S., Acharyya, S., Chen, L., Aldous, J., Schurman, N., Baladandayuthapani, V., Frankel, T. L., Salami, S. S., Manley, B. J., Mehra, R., Udager, A. M., Keller, E. T.. 2025-06-14. Spatial analysis reveals a novel inflammatory tumor transition state which promotes a macrophage-driven induction of sarcomatoid renal cell carcinoma. https://doi.org/10.1101/2025.06.12.656421

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