Abstract LB245: Collagen remodeling promotes a GPCR-mediated mechanosensory immune checkpoint in ADGRG1+ CD8+ T cells and serves as a spatial biomarker of response to immunotherapy

Abstract Accessibility of immune cells to the tumor microenvironment (TME) in many solid tumors can be influenced by extracellular matrix (ECM) deposition, organization, and remodeling within tumor stroma. Specifically, lysyl hydroxylase-2 (LH2)-catalyzed lysine hydroxylation in type-I collagen telopeptides leads to formation of intermolecular collagen cross-links creating a stiffened and proteolytically resistant, stable ECM. Advanced head and neck squamous cell carcinomas (HNSCC) frequently exhibit desmoplasia with elevated LH2 expression, and Immune-checkpoint (ICI) therapy is effective in only <20% patients, suggesting that ECM remodeling mechanistically governs the composition and function of TME infiltrates. We show that elevated LH2 and collagen alignment promotes stromal accumulation of CD8⁺ T-cells, and poor response to ICI in HPV-HNSCCs. Integration of clinical biopsies, transcriptomic datasets, and an immunocompetent syngeneic mouse model revealed that aligned collagen spatially restricts adhesion G protein-coupled receptor positive (ADGRG1⁺) CD8⁺ T-cells to activate a non-canonical GPCR-mediated mechanosensory program that drives dysfunction and exhaustion. Citation Format: Sonal Srivastava, John J. Powers, Jay H. Mehta, Sadegh Marban, Ryunosuke Nozaki, Laxmi Swetha Karanam, Jacob Torrez, Harish S. Bharambe, Farhoud Faraji, Ritu Chaudhary, Pino Bordignon, Jacqueline Giliberti, Robbert J. Slebos, Joseph O. Johnson, Chandler Gantenbee, Xiaofei Song, Marco Cassano, Jose A. Guevara-Patino, Duy T. Nguyen, Alexander R. Anderson, Mitsuo Yamauchi, Jeffery West, J Silvio Gutkind, Christine H. Chung, Antonio L. Amelio. Collagen remodeling promotes a GPCR-mediated mechanosensory immune checkpoint in ADGRG1+ CD8+ T cells and serves as a spatial biomarker of response to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB245.