Mechanisms of Dual Inhibition of TGFbeta/PD-L1 in HNSCC

TGFbeta/PD-L1 在 HNSCC 中的双重抑制机制

基本信息

批准号：
10620449
负责人：
Jing Hong Wang
金额：
$ 45.08万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-11 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10620449
关键词：
Antibodies Antigens Antitumor Response Attenuated CD8B1 gene Cell Line Cells Characteristics Clinical Trials Data Distant Metastasis Epithelial FDA approved Future Genetic Genetically Engineered Mouse Goals Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Head and neck structure Human ITGAM gene Immune Immunocompetent Immunosuppression Immunosuppressive Agents Immunotherapeutic agent Immunotherapy Inflammation Inflammatory Investigational Therapies Leukocytes Malignant Neoplasms Mediating Mediator of activation protein Metastatic Neoplasm to the Lung Modeling Molecular Profiling Molecular Target Mus Myeloid Cells Myeloid-derived suppressor cells Neoplasm Metastasis Nude Mice Outcome PDL1 inhibitors Patient Selection Patients Pharmacodynamics Plasma Population Prediction of Response to Therapy Primary Neoplasm Recurrence Relapse Reporting Resistance Sampling Signal Transduction Smoker Specimen Squamous Cell Lung Carcinoma Squamous cell carcinoma T cell clonality T memory cell T-Lymphocyte Testing The Cancer Genome Atlas Therapeutic Agents Therapeutic Effect Therapeutic Intervention Therapeutic Uses Tobacco Transforming Growth Factor beta Transforming Growth Factors Transplantation Treatment Efficacy Tumor Subtype Tumor Suppressor Proteins Tumor-Infiltrating Lymphocytes anti-PD-L1 anti-tumor immune response base biomarker-driven cancer transplantation cellular targeting chemokine cytokine design efficacy testing inhibitor inhibitor therapy insight memory CD4 T lymphocyte molecular marker mouse model mutant new therapeutic target next generation novel novel therapeutic intervention novel therapeutics overexpression patient derived xenograft model patient population programmed cell death ligand 1 programmed cell death protein 1 response therapeutic development tool treatment response tumor tumor microenvironment

项目摘要

SUMMARY Squamous cell carcinoma (SCC) accounts for over 90% of head and neck (HN) cancer. HNSCCs in heavy smokers respond poorly to therapies and have the highest rate of relapse/recurrence among all HNSCC patients. Inhibitors of programmed death-1 (PD-1) are FDA approved to treat relapsed/recurrent HNSCCs, but are only effective in ~25% of HNSCCs, indicating additional immune suppressive/evasion mechanisms. We reported that transforming growth factor-β1 (TGFβ1), an immune suppressor, is elevated in >60% of tobacco- associated HNSCCs. Unique to HNSCC, TGFβ1 causes excessive inflammation with the majority of tumor infiltrating leukocytes being myeloid cells. Developing new therapeutic interventions that effectively target these tumor microenvironment (TME) characteristics is hindered by a dearth of HNSCC models with metastatic potential in an immune competent background. This application employs new therapeutic agents to target both PD-L1 and TGFβ in HNSCC and metastasis, and analyze the underlying mechanisms. We have created a mouse model in which Smad4, a tumor suppressor frequently lost in tobacco-associated HNSCCs, is deleted (Smad4-/-) in head and neck epithelia. Smad4 loss causes SCC and metastasis, and compensatory TGFβ1 overproduction. Preliminary data revealed that Smad4-/- SCCs also overexpress PD-L1 and short-term TGFβ inhibition sensitized SCCs to anti-PD-L1. Further, in mice with SCC eradicated, re-transplanting the same SCC cell line failed to initiate new tumors, suggesting a memory T cell-dependent anti-tumor response. TGFβ inhibition also reduced SCC lung metastases in immune compromised mice. Taken together, we hypothesize that attenuating a TGFβ-induced immune suppressive and inflammatory TME in Smad4 mutant HNSCCs makes immunotherapy more effective, thus dual TGFβ/PD-L1 inhibition eradicates these HNSCCs via T-cell-dependent and -independent mechanisms. Aim 1 will perform experimental therapeutics using novel TGFβ/PD-L1 inhibitor drugs on genetic mouse models and transplanted human HNSCCs to determine if Smad4 loss and TGFβ1 overexpression predict therapeutic response to TGFβ/PD-L1 dual inhibition in HNSCCs in immune competent and compromised conditions. Aim 2 will assess T cell- dependent mechanisms of TGFβ inhibition on sensitizing or synergizing with anti-PD-L1-mediated SCC eradication, utilizing tumors generated in Aim 1 and patient HNSCC specimens to examine if Smad4 loss and TGFβ/PD-L1 levels correlate with immune suppressive T cell profiles. Aim 3 will use tumors generated in Aim 1 to assess if myeloid cell-dependent targeting effects of TGFβ/PD-L1 inhibition contribute to therapeutic efficacy in HNSCC and metastasis, and patient HNSCC specimens to examine if Smad4 loss and TGFβ/PD-L1 levels correlate with increased myeloid cells and associated molecular markers. These studies will lead to a novel therapeutic strategy for HNSCC patients with high rates of recurrence and metastasis. Additionally, the mechanistic studies will offer novel insights into future biomarker-driven selection for future clinical trials of TGFβ/PD-L1 dual inhibition in HNSCC patients.

概括鳞状细胞癌（SCC）占头颈（HN）癌症的90％以上。 hnsccs沉重吸烟者对疗法的反应不佳，并且在所有HNSCC中的救济/复发率最高患者。批准了编程死亡1（PD-1）的抑制剂（PD-1）来治疗复发/经常性HNSCC，但仅在约25％的HNSCC中有效，表明额外的免疫抑制/逃避机制。我们据报道，在烟草中，转化生长因子-β1（TGFβ1）是一种免疫抑制剂，升高相关的HNSCC。 HNSCC独有的TGFβ1引起大多数肿瘤的过度炎症浸润白细胞是髓样细胞。开发有效针对这些的新的治疗干预措施肿瘤微环境（TME）特性受到转移性HNSCC模型的死亡的阻碍在免疫胜任背景下的潜力。该申请员工新的治疗剂，以针对 HNSCC和转移中的PD-L1和TGFβ，分析潜在机制。我们创建了一个鼠标模型是删除与烟草相关的HNSCC中经常丢失的肿瘤抑制剂的SMAD4。（smad4 - / - ）头部和颈部上皮。 SMAD4损失导致SCC和转移，代偿性TGFβ1 生产过剩。初步数据表明，Smad4 - / - SCC也过表达PD-L1和短期TGFβ 对抗PD-L1的抑制敏感SCC。此外，在带有RadiOdicated的小鼠中，重新移植了相同的SCC 细胞系未能引发新的肿瘤，表明记忆T细胞依赖性抗肿瘤反应。 TGFβ 抑制作用还降低了免疫受损小鼠中的SCC肺转移。总之，我们假设减弱了TGFβ诱导的免疫抑制和炎症TME HNSCCS使免疫疗法更有效，因此双重TGFβ/PD-L1抑制放射线 HNSCC通过T细胞依赖性和非依赖性机制。 AIM 1将执行实验在遗传小鼠模型上使用新型TGFβ/PD-L1抑制剂药物的治疗和移植的人 HNSCCS确定SMAD4损失和TGFβ1的过表达是否预测对TGFβ/PD-L1的治疗反应在免疫能力和受损条件下，HNSCCS双重抑制。 AIM 2将评估T细胞 - TGFβ抑制对抗PD-L1介导的SCC敏感或协同作用的依赖机制根除，利用AIM 1和患者HNSCC标本中产生的肿瘤检查SMAD4丢失和是否丢失和 TGFβ/PD-L1水平与免疫抑制T细胞谱相关。 AIM 3将使用AIM产生的肿瘤 1评估TGFβ/PD-L1抑制的髓样细胞依赖性靶向作用是否有助于治疗 HNSCC和转移的功效，以及患者HNSCC标本以检查SMAD4丢失和TGFβ/PD-L1是否水平与增加的髓样细胞和相关的分子标记相关。这些研究将导致 HNSCC复发率和转移率高的HNSCC患者的新型理论策略。另外，机械研究将为未来的生物标志物驱动选择提供新的见解，以供未来的临床试验 HNSCC患者的TGFβ/PD-L1双重抑制。