HLA-E and NKG2A define a novel immune checkpoint axis in non-muscle-invasive bladder cancer

HLA-E 和 NKG2A 定义了非肌层浸润性膀胱癌的新型免疫检查点轴

• 批准号: 10587009
• 负责人: Amir Horowitz
• 金额: $ 68.61万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587009
• 关键词: Antineoplastic Agents; BCG Live; Bacillus Calmette-Guerin Therapy; Binding; Bladder Neoplasm; Blocking Antibodies; Blood; Blood specimen; CD8-Positive T-Lymphocytes; Carcinoma in Situ; Cells; Chronic; Clinical; Clinical Trials; Coculture Techniques; Combination immunotherapy; Complex; Cytolysis; Cytometry; Data; Disease; Disease Progression; Dose; Exposure to; FDA approved; Financial Hardship; Genes; Genetic; Geographic Locations; Goals; Hematopoietic; Image; Immune; Immune response; Immunofluorescence Immunologic; Immunologic Factors; Immunotherapy; Improve Access; In Vitro; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Interferon Type II; Intravesical Instillation; KLRD1 gene; Kinetics; Link; Major Histocompatibility Complex; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Maps; Measures; Mediating; Modeling; Molecular Profiling; Mycobacterium bovis; Natural Killer Cells; Newly Diagnosed; Organoids; PD-1 pathway; PD-1/PD-L1; PD-L1 blockade; Pathway interactions; Patient Care; Patients; Peripheral; Phenotype; Population; Primary Neoplasm; Proteins; Recruitment Activity; Recurrence; Recurrent disease; Recurrent tumor; Regimen; Resistance; Role; Signal Transduction; Specimen; Stromal Cells; T-Lymphocyte; Technology; Testing; Therapeutic; Tumor Immunity; Tumor Tissue; Tumor-Derived; Tumor-Infiltrating Lymphocytes; Work; anti-PD-L1; cancer diagnosis; cancer type; chemokine; cytokine; dosage; exhaust; exhaustion; experience; functional restoration; functional status; high risk; immune checkpoint; immune checkpoint blockade; immunological status; improved; intravesical; mouse model; neoplastic cell; new therapeutic target; non-muscle invasive bladder cancer; novel; peripheral blood; predictive marker; profiles in patients; programmed cell death ligand 1; programmed cell death protein 1; recruit; resistance mechanism; response; spatiotemporal; therapy resistant; transcriptome sequencing; transcriptomics; tumor; tumor diagnosis; tumor microenvironment; tumor progression; virtual

Bladder cancer is the most expensive cancer per capita to treat in the US. Non-muscle invasive bladder cancer (NMIBC) which accounts for 70-75% of all newly diagnosed tumors and has only a single FDA approved first- line treatment option, Bacillus Calmette-Guérin (BCG). BCG has been the only approved first-line therapy for intermediate and high-risk NMIBC for more than 40 years. While BCG can induce durable responses, ~50% of patients have recurrence or progression of their disease. The current dosing of BCG is arbitrary with no data currently available to support the dosage, strain nor regimen. Furthermore, no clear mechanism of action behind BCG’s anti-neoplastic activity in NMIBC has been delineated. Better understanding of the immune response initiated by exposure to BCG and how such response is sustained over many repeated doses is essential to help improve its therapeutic action. Further, it may lead to discovery of predictive biomarkers and novel targets leading to advance care for patients, reduce the financial burden associated with the disease, and improve access to BCG. Our preliminary data have identified a significant Type-1 cytokine response to BCG in all patients inducing an activation and recruitment of IFN-g producing NKG2A+ natural killer (NK) cells and NKG2A+PD-1+ CD8 T cells to the tumor microenvironment (TME). Our preliminary analyses of post-BCG-treated specimens demonstrate IFN-g signaling as the most upregulated signature in BCG resistant specimens and strongly correlates with increased HLA-E and PD-L1 expression on the recurring tumors. Monalizumab (anti-NKG2A) is a novel therapeutic target and is currently in clinical trials across several cancer types. A role for NKG2A/HLA-E alone or in conjunction with PD-1/PD-L1 in regulating NK and CD8 T cells remains elusive with virtually nothing known in bladder cancer. Our hypothesis is that chronic activation from repeated exposures to BCG drives immune dysregulation followed by functional exhaustion in a significant proportion of patients, which then leads to disease recurrence or progression. The immune dysregulation in the TME is driven by NKG2A/PD-1 on CD8 T cells, NKG2A on NK cells and HLA-E and PD-L1 on tumor cells. To further validate our findings and better understand BCG mechanisms we will study the following aims: Aim 1: To analyze intratumoral NK cells and T cells and their interactions with tumors in response to BCG therapy. We will test the hypothesis that upregulated expression of HLA-E and PD-L1 on recurring tumors are directly in contact with infiltrating NKG2A+ NK and NKG2A+ PD-1+ CD8 T cells. Aim 2: To longitudinally assess blood and tumor phenotypes and functions in response to BCG therapy. We will test the hypothesis that repeated exposures to BCG drives prolonged activation and dysregulation of NKG2A+ NK and NKG2A+ PD-1+ CD8 T cells. Aim 3: To determine the effects of combination PD-L1 and NKG2A blockade on anti-tumor immunity. We will test the hypothesis that NKG2A+ NK and NKG2A+ PD-1+ CD8 T cells can be functionally restored through use of PD-L1 and NKG2A combination blockade.

膀胱癌是美国治疗的人均癌症。非肌肉侵入性膀胱癌 （NMIBC）占所有新诊断肿瘤的70-75％，并且只有一个FDA批准的 线治疗选项，杆菌Calmette-guérin（BCG）。 BCG是唯一获得批准的一线疗法 中级和高风险NMIBC超过40年。虽然BCG可以诱导持久的响应，但约有50％ 患者患有疾病的复发或进展。当前的BCG剂量是任意的，没有数据 目前可用于支持剂量，劳累或方案。此外，背后没有明确的行动机制 已经划定了BCG在NMIBC中的抗肿瘤活性。更好地理解免疫反应 通过暴露于BCG发起以及如何在许多重复剂量上持续这种反应对于帮助 改善其治疗作用。此外，这可能导致发现预测性生物标志物和新目标领先 为了改善患者的护理，减少与疾病相关的经济燃烧，并提高进入 BCG。我们的初步数据已经确定了所有诱导的患者对BCG的显着1型细胞因子反应 IFN-G产生NKG2A+天然杀伤（NK）细胞和NKG2A+ PD-1+ CD8 T细胞的激活和募集 到肿瘤微环境（TME）。我们对BCG后处理的标本的初步分析证明了 IFN-G信号传导是BCG抗性标本中最新更新的签名，并且与 在复发性肿瘤上增加了HLA-E和PD-L1的表达。 monalizumab（抗NKG2A）是一部小说 治疗靶标，目前正在几种癌症类型的临床试验中。仅NKG2A/HLA-E的角色 或与调节NK和CD8 T细胞中的PD-1/PD-L1结合使用，几乎没有任何已知的 在膀胱癌中。我们的假设是，从重复暴露到BCG的慢性激活使免疫 失调，然后在很大一部分患者中进行功能精疲力尽，然后导致疾病 复发或进展。 TME中的免疫失调由CD8 T细胞上的NKG2A/PD-1驱动， NKG2A在NK细胞上，HLA-E和PD-L1上的NKG2A在肿瘤细胞上。进一步验证我们的发现并更好地理解 BCG机制我们将研究以下目的：目标1：分析肿瘤内NK细胞和T细胞及其其 响应BCG治疗的肿瘤相互作用。我们将测试以下假设 重复肿瘤上的HLA-E和PD-L1直接与浸润的NKG2A+ NK和NKG2A+ PD-1+接触 CD8 T细胞。目标2：纵向评估血液和肿瘤表型以及对BCG的功能 治疗。我们将测试以下假设，即反复暴露于BCG会驱动延长激活和 NKG2A+ NK和NKG2A+ PD-1+ CD8 T细胞的失调。目标3：确定组合的影响 PD-L1和NKG2A抗肿瘤免疫的阻塞。我们将测试NKG2A+ NK和NKG2A+的假设 PD-1+ CD8 T细胞可以通过使用PD-L1和NKG2A组合阻滞来恢复功能。