LBPO.TB01 · 肿瘤生物学 · Late-Breaking

胶原重塑促进ADGRG1+ CD8+ T细胞中一种GPCR介导的机械感觉免疫检查点并作为免疫治疗应答的空间生物标志物

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 Authors & Affiliations

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

中文摘要

在许多实体瘤中，免疫细胞对肿瘤微环境（TME）的可及性可受到肿瘤基质内细胞外基质（ECM）沉积、组织和重塑的影响。具体而言，赖氨酰羟化酶-2（LH2）催化的I型胶原端肽中的赖氨酸羟化导致分子间胶原交联的形成，产生僵硬且抗蛋白水解、稳定的ECM。晚期头颈部鳞状细胞癌（HNSCC）常表现出伴LH2表达升高的促结缔组织增生，而免疫检查点抑制剂（ICI）疗法仅在<20%的患者中有效，提示ECM重塑在机制上支配TME浸润物的组成和功能。我们表明，LH2升高和胶原排列促进CD8⁺ T细胞的基质积聚，以及HPV-HNSCC中对ICI的不良应答。整合临床活检、转录组数据集和免疫健全的同基因小鼠模型显示，排列的胶原在空间上将黏附G蛋白偶联受体阳性（ADGRG1⁺）CD8⁺ T细胞限制起来，以激活一种非经典的GPCR介导的机械感觉程序，进而驱动功能障碍和耗竭。

查看英文原文 English 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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