Targeting the CD73-adenosinergic pathway in head and neck cancer

靶向头颈癌中的 CD73 腺苷能通路

• 批准号: 10813613
• 负责人: YAN CUI
• 金额: $ 68.61万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10813613
• 关键词: 5' -Nucleotidase; ADORA2A gene; Adenosine; Affect; Alcohol consumption; Biological; CTLA4 gene; Cancer Model; Carcinogens; Cell Death; Cell surface; Cells; Clinical; Clinical Research; Dendritic Cells; Development; Disease Progression; Enzymes; Evolution; Fibroblasts; Genetically Engineered Mouse; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Health; Human; Hypoxia; Immune; Immunosuppression; Individual; Lead; Leukocytes; Link; Macrophage; Malignant Neoplasms; Mediating; Modality; Modeling; Mouse Strains; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Myeloproliferative disease; Natural Killer Cells; Outcome; PD-1/PD-L1; Pathway interactions; Patients; Pattern; Postoperative Period; Pre-Clinical Model; Productivity; Public Health; Purinergic P1 Receptors; Radial; Radiation therapy; Receptor Cell; Regimen; Role; Sampling; Specimen; T-Cell Activation; T-Lymphocyte; Testing; The Cancer Genome Atlas; Therapeutic; Therapeutic Intervention; Tobacco use; Tongue; Toxic effect; Tumor Immunity; Validation; advanced disease; cancer therapy; chemoradiation; cohort; extracellular; high dimensionality; immune checkpoint; immune checkpoint blockade; immunosuppressed; improved; insight; malignant mouth neoplasm; neoplastic cell; oral HPV-positive head and neck cancers; oral tissue; patient subsets; peripheral blood; pre-clinical; receptor; small molecule inhibitor; spatial relationship; therapy outcome; tool; translational approach; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions

Head and neck squamous cell carcinoma (HNSC) related to tobacco and alcohol consumption is aggressive and responds poorly to available therapy. Even the new PD-1/PD-L1 immune checkpoint blockade is insufficient to control progression due to other highly immunosuppressive conditions in the tumor microenvironment (TME). Compelling evidence implicates the ecto-5'-nucleotidase (NT5E) CD73 as another important immune checkpoint, as high CD73 expression in the TME of many tumors, including HNSC, is linked to poor patient survival. Several consistent TME conditions, such as hypoxia and treatment, cause an increase in extracellular (e)ATP, and CD73 serves at the last, rate-limiting step in concert with CD39 and other ectoenzymes, to convert eATP to adenosine (eADO). eADO activates adenosine receptor (AR) A2AR to suppress T cell activation, while A2BR promotes immunosuppression via cancer-associated fibroblasts (CAF) and myeloid cells present in the TME. Studies, including our own, show that CD73 and A2BR, and to a lesser extent A2AR, are expressed in the highly immunosuppressive TME of progressive HNSC of both clinical and preclinical samples, suggesting their role in the immunosuppression. However, the contributions of molecules downstream of CD73 are poorly understood. Recent rapid advances in spatial analysis of the TME have revealed a critical role of immune effector to target cell distance in generating productive antitumor immunity with impact on clinical outcomes. Because eADO is short-lived, the spatial relationship between CD73 on one hand and A2AR or A2BR on the other hand, is likely to affect the specific AR activated by eADO. We discovered in HNSC clinical specimens that A2AR is rather limited and located remotely from CD73, which supports the hypothesis that the major immunosuppressive impact of CD73-AR immune checkpoint is mediated primarily through the CD73-A2BR axis. Our plan is to: (1) dissect how the CD73-A2BR pathway regulates the immune landscape in the TME of ectopic preclinical HNSC models during progression and treatment; (2) develop effective CD73-ADO-A2BR ICB regimens in preclinical models of orthotopic and in primary carcinogen-induced tongue HNSC; (3) assess the relationships between HNSC patient peripheral blood myeloid precursors, levels and distribution of CD73 and A2BR on myeloid and CAF subsets in the TME, patients’ three-year post-operative outcomes. Impact: The proposed study will identify CD73-A2BR-dependent mechanisms of immunosuppression in HNSC preclinical models and develop translatable therapeutic intervention. The results will provide highly valuable insights into the effects of CD73-A2BR axis on disease progression and the therapeutic potential of blocking it.

与吸烟和饮酒有关的头颈部鳞状细胞癌（HNSC）具有侵袭性， 对现有治疗反应不佳。即使是新的PD-1/PD-L1免疫检查点阻断也不足以 控制由于肿瘤微环境（TME）中其他高度免疫抑制条件导致的进展。 令人信服的证据表明，外-5 '-核苷酸酶（NT 5E）CD 73是另一个重要的免疫检查点， 因为许多肿瘤（包括HNSC）的TME中的高CD 73表达与患者存活率差有关。 几种一致的TME条件，如缺氧和治疗，导致细胞外（e）ATP增加， 而CD 73在最后一个限速步骤中与CD 39和其他胞外酶一起将eATP转化为 腺苷（eADO）。eADO激活腺苷受体（AR）A2 AR以抑制T细胞活化，而A2 BR 通过TME中存在的癌症相关成纤维细胞（CAF）和骨髓细胞促进免疫抑制。 包括我们自己的研究在内的研究表明，CD 73和A2 BR，以及在较小程度上的A2 AR，在高表达的细胞中表达。 临床和临床前样品的进行性HNSC的免疫抑制性TME，表明它们在 免疫抑制然而，CD 73下游分子的贡献知之甚少。 最近在TME的空间分析方面的快速进展揭示了免疫效应物对靶的关键作用 细胞距离产生有效的抗肿瘤免疫力，对临床结果有影响。因为eADO是 短暂的，一方面CD 73和另一方面A2 AR或A2 BR之间的空间关系，可能 影响由eADO激活的特定AR。我们在HNSC临床标本中发现，A2 AR是相当有限的 并且远离CD 73，这支持了以下假设： CD 73-AR免疫检查点主要通过CD 73-A2 BR轴介导。 我们的计划是：（1）分析CD 73-A2 BR通路如何调节异位妊娠TME中的免疫景观。 进展和治疗期间的临床前HNSC模型;（2）开发有效的CD 73-ADO-A2 BR ICB方案 在原位和原发性致癌物诱导的舌HNSC的临床前模型中;（3）评估 HNSC患者外周血髓系前体细胞、髓系上CD 73和A2 BR的水平和分布之间 TME中CAF和CAF亚群，患者术后3年结局。 影响：拟议的研究将确定HNSC中的CD 73-A2 BR依赖性免疫抑制机制 临床前模型和开发可翻译的治疗干预。这些结果将为我们提供非常有价值的 深入了解CD 73-A2 BR轴对疾病进展的影响以及阻断它的治疗潜力。