LBPO.TB01 · 肿瘤生物学 · Late-Breaking

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

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

编号 LB245 展板 20 时间 4/20 02:00–05:00 区域 Section 55 主讲 Sonal Srivastava, PhD

分会场 Late-Breaking Research: Tumor Biology 1

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作者与单位

Sonal Srivastava¹, John J. Powers¹, Jay H. Mehta¹, Sadegh Marban¹, Ryunosuke Nozaki², Laxmi Swetha Karanam¹, Jacob Torrez¹, Harish S. Bharambe¹, Farhoud Faraji³, Ritu Chaudhary¹, Pino Bordignon⁴, Jacqueline Giliberti⁵, Robbert J. C. Slebos¹, Joseph O. Johnson¹, Chandler Gantenbee¹, Xiaofei Song¹, Marco Cassano⁴, Jose A. Guevara-Patino¹, Duy T. Nguyen¹, Alexander R. A. Anderson¹, Mitsuo Yamauchi², Jeffery West¹, J. Silvio Gutkind³, Christine H. Chung¹, Antonio L. Amelio¹

¹Moffitt Cancer Center, Tampa, FL,²Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC,³Department of Otolaryngology-Head and Neck Surgery, UC San Diego Health,, La Jolla, CA,⁴Bio-Techne, Lunaphore Technologies SA, Tolochenaz, Switzerland,⁵Bio-Techne, Advanced Cell Diagnostics, Newark, CA

摘要 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.

利益披露 Disclosure

S. Srivastava, None.. J. J. Powers, None.. J. H. Mehta, None.. S. Marban, None.. R. Nozaki, None.. L. S. Karanam, None.. J. Torrez, None.. H. S. Bharambe, None.. F. Faraji, None.. R. Chaudhary, None. P. Bordignon, Bio-Techne Employment, Stock. J. Giliberti, Bio-Techne Employment. R. J. C. Slebos, Exelixis Other, Honoraria for Scientific Advisory Board. Fulgent Other, Honoraria for Scientific Advisory Board. Genmab Other, Honoraria for Scientific Advisory Board. AVEO Other, Honoraria for Scientific Advisory Board. Seagen Other, Honoraria for Scientific Advisory Board. Regeneron Other, Honoraria for Scientific Advisory Board. Bicara Other, Honoraria for Scientific Advisory Board. Johnson and Johnson Other, Honoraria for Scientific Advisory Board. J. O. Johnson, None.. C. Gantenbee, None.. X. Song, None. M. Cassano, Bio-Techne Employment, Stock. J. A. Guevara-Patino, None.. D. T. Nguyen, None.. A. R. A. Anderson, None.. M. Yamauchi, None.. J. West, None.. J. S. Gutkind, None. C. H. Chung, Exelixis Other, Honoraria for Scientific Advisory Board. Fulgent Other, Honoraria for Scientific Advisory Board. Genmab Other, Honoraria for Scientific Advisory Board. AVEO Other, Honoraria for Scientific Advisory Board. Seagen Other, Honoraria for Scientific Advisory Board. Regeneron Other, Honoraria for Scientific Advisory Board. Bicara Other, Honoraria for Scientific Advisory Board. Johnson and Johnson Other, Honoraria for Scientific Advisory Board. A. L. Amelio, None.

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