Key Regulatory Elements of the TGFbeta-LRRC15 Axis Predict Disease Progression and Immunotherapy Resistance Across Cancer Types

Storey, C. M.; Cheng, M.; Altai, M.; Park, J. E.; Tran, J.; Lueong, S. S.; Thorek, D. L.; Mao, L.; Zedan, W.; Yuen, C.; Ridley, A.; Trajkovic-Arsic, M.; Herrmann, K.; Subudhi, S. K.; Siddiqui, B. A.; Lueckerath, K.; Siveke, J.; Damoiseaux, R.; Yang, X.; Ulmert, D.

doi:10.1101/2024.11.22.624939

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bioRxiv · 10.1101/2024.11.22.624939

Key Regulatory Elements of the TGFbeta-LRRC15 Axis Predict Disease Progression and Immunotherapy Resistance Across Cancer Types

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Abstract

Transforming growth factor-beta (TGF{beta}) has dual roles in cancer, initially suppressing tumors but later promoting metastasis and immune evasion. Efforts to inhibit TGF{beta} have been largely unsuccessful due to significant toxicity and indiscriminate immunosuppression. Leucine-rich repeat-containing protein 15 (LRRC15) is a TGF{beta}-regulated antigen expressed by mesenchymal-derived cancer cells and cancer-associated fibroblasts (CAFs). In preclinical studies, ablation of TGF{beta}-driven LRRC15+ CAFs increased tumor infiltration of CD8+ T cells. However, the underlying pathobiological mechanisms prompting TGF{beta}s upregulation of LRRC15 expression are unclear. Using an integrated approach combining functional compound screening with single-cell RNA sequencing, we reveal key genomic features regulating TGF{beta}s ability to increase LRRC15 expression on cancer cells. Construction of gene regulatory networks converged our analyses on four key genes--MMP2, SPARC, TGF{beta}R2, and WNT5B--central to TGF{beta}-induced LRRC15 pathobiology. Validation of these genes in cell models and their use in predicting immunotherapy responses highlight their potential in refining immunotherapy strategies and personalizing co-treatment options.

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Storey, C. M., Cheng, M., Altai, M., Park, J. E., Tran, J., Lueong, S. S., Thorek, D. L., Mao, L., Zedan, W., Yuen, C., Ridley, A., Trajkovic-Arsic, M., Herrmann, K., Subudhi, S. K., Siddiqui, B. A., Lueckerath, K., Siveke, J., Damoiseaux, R., Yang, X., Ulmert, D.. 2024-11-25. Key Regulatory Elements of the TGFbeta-LRRC15 Axis Predict Disease Progression and Immunotherapy Resistance Across Cancer Types. https://doi.org/10.1101/2024.11.22.624939

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