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.

膀胱癌是美国人均治疗费用最高的癌症。非肌层浸润性膀胱癌 （NMIBC）占所有新诊断肿瘤的70-75%，并且只有一个FDA首先批准- 线治疗选项，卡介苗（BCG）。BCG是唯一被批准的一线治疗药物， 40多年来一直是中等和高风险的NMIBC。虽然BCG可以诱导持久的反应，但约50%的 患者的疾病复发或进展。目前卡介苗的剂量是任意的，没有数据 目前可用于支持剂量、菌株或方案。此外，背后没有明确的作用机制 BCG在NMIBC中的抗肿瘤活性已经被描述。更好地理解免疫反应 以及这种反应如何在多次重复给药后持续，对于帮助 提高其治疗作用。此外，它可能导致发现预测性生物标志物和新的靶标， 提高对患者的护理，减轻与疾病相关的经济负担，并改善获得 卡介苗。我们的初步数据已经确定了在所有患者中对BCG的显著的1型细胞因子应答， 产生IFN-g的NKG 2A+自然杀伤（NK）细胞和NKG 2A +PD-1+ CD 8 T细胞的活化和募集 肿瘤微环境（TME）我们对卡介苗治疗后标本的初步分析表明， IFN-g信号是BCG耐药标本中上调最多的信号，与 复发肿瘤上HLA-E和PD-L1表达增加。Monalizumab（抗NKG 2A）是一种新的 目前正在几种癌症类型的临床试验中。NKG 2A/HLA-E单独的作用 或与PD-1/PD-L1联合调节NK和CD 8 T细胞仍然难以捉摸， 在膀胱癌中。我们的假设是，反复暴露于BCG的慢性激活会驱动免疫系统， 在很大比例的患者中，调节失调，随后功能衰竭，然后导致疾病 复发或进展。TME中的免疫失调由CD 8 T细胞上的NKG 2A/PD-1驱动， NK细胞上的NKG 2A和肿瘤细胞上的HLA-E和PD-L1。为了进一步验证我们的发现， 本课题主要研究BCG的作用机制：目的1：分析肿瘤内NK细胞和T细胞及其相互关系， 与肿瘤的相互作用对BCG治疗的反应。我们将检验一个假设， 复发肿瘤上的HLA-E和PD-L1与浸润性NKG 2A + NK和NKG 2A + PD-1+直接接触 CD 8 T细胞。目的2：纵向评估血液和肿瘤表型和功能对BCG的反应 疗法我们将检验这样一个假设，即反复接触卡介苗会延长激活时间， NKG 2A + NK和NKG 2A + PD-1+ CD 8 T细胞失调。目的3：确定联合用药的效果 PD-L1和NKG 2A阻断抗肿瘤免疫。我们将检验NKG 2A + NK和NKG 2A + PD-1+ CD 8 T细胞可以通过使用PD-L1和NKG 2A联合阻断功能恢复。