ABSTRACT
Transforming growth factor-beta (TGFβ) has dual roles in cancer, initially suppressing tumors but later promoting metastasis and immune evasion. Efforts to inhibit TGFβ have been largely unsuccessful due to significant toxicity and indiscriminate immunosuppression. Leucine-rich repeat-containing protein 15 (LRRC15) is a TGFβ-regulated antigen expressed by mesenchymal-derived cancer cells and cancer-associated fibroblasts (CAFs). In preclinical studies, ablation of TGFβ-driven LRRC15+ CAFs increased tumor infiltration of CD8+ T cells. However, the underlying pathobiological mechanisms prompting TGFβ’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 TGFβ’s ability to increase LRRC15 expression on cancer cells. Construction of gene regulatory networks converged our analyses on four key genes—MMP2, SPARC, TGFβR2, and WNT5B—central to TGFβ-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.
Competing Interest Statement
DU, RD, and CMS are inventors on a patent application submitted by UCLA that covers radiotheranostic applications of DUNP19. KH and DU serve as board members on Radiopharm Theranostics Scientific Advisory board, which has licensed DUNP19 for radiotheranostic use. DU and DT serve as scientific advisors to Curium. DU reports receiving grants from Radiopharm Theranostics and Janssen Pharmaceuticals outside the submitted work. Additionally, DU has patents EP2771688A4 and EP3297669A1 issued. DU also reports receiving grants from the Prostate Cancer Foundation and the Department of Defense during the conduct of the study. DU is a founder of and consultant to Diaprost AB and holds stock in the company. Further, DU has received a speakers honorarium from Janssen R&D LLC and personal fees from Curium, Molecular Partners, AstraZeneca, and Ferring outside the submitted work. KL reports personal fees from Sofie Biosciences, Avidity Partner, B Capital, and research grants from Novartis, AMGEN, Debiopharm, and Mariana Oncology outside the submitted work. RD reports personal fees from Amgen, Panorama Medicine, and Epirium Bio outside the submitted work. JTS receives honoraria as consultant or for continuing medical education presentations from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Immunocore, MSD Sharp Dohme, Novartis, Roche/Genentech, and Servier. His institution receives research funding from Abalos Therapeutics, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eisbach Bio, and Roche/Genentech; he holds ownership in FAPI Holding (<D 3%D); all outside the submitted work. No disclosures were reported by the other authors.
