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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：
10541103
负责人：
Jing Hong Wang
金额：
$ 52.37万
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 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10541103
关键词：
Antibodies Antigens Antitumor Response Attenuated CD8B1 gene Cell Line Cells Characteristics Clinical Trials Data Distant Metastasis Epithelium 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 Leucocytic infiltrate Leukocytes Malignant Neoplasms Mediating Mediator 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 Production Recurrence Relapse Reporting Resistance Sampling Signal Transduction Smoker Specimen 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 biomarker driven cancer transplantation cellular targeting chemokine cytokine design effective intervention efficacy testing human cancer mouse model 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 retransplantation synergism therapeutic development tool treatment response tumor tumor initiation 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.

总结鳞状细胞癌（SCC）占头颈部（HN）癌症的90%以上。HNSCC在重度吸烟者对治疗反应差，在所有HNSCC中复发率最高患者程序性死亡-1（PD-1）的抑制剂被FDA批准用于治疗复发/再发HNSCC，但仅在~25%的HNSCC中有效，表明另外的免疫抑制/逃避机制。我们报道，转化生长因子β1（TGFβ1），一种免疫抑制因子，在>60%的烟草中升高，相关的HNSCC。HNSCC特有的TGFβ1引起大多数肿瘤的过度炎症，浸润性白细胞是骨髓细胞。开发新的治疗干预措施，有效地针对这些肿瘤微环境（TME）特征受到缺乏转移性HNSCC模型的阻碍，在免疫能力强的背景下。该应用采用新的治疗剂来靶向 PD-L1和TGFβ在HNSCC及转移中的作用，并分析其机制。我们创建了一个 Smad 4（一种在烟草相关HNSCC中经常丢失的肿瘤抑制因子）缺失的小鼠模型（Smad4-/-）。Smad 4缺失导致SCC和转移，而代偿性TGFβ1 生产过剩。初步数据显示，Smad 4-/-SCC也过表达PD-L1和短期TGFβ，抑制使SCC对抗PD-L1敏感。此外，在SCC根除的小鼠中，再次移植相同的SCC 细胞系未能引发新的肿瘤，表明记忆T细胞依赖性抗肿瘤应答。转化生长因子β 抑制还减少免疫受损小鼠中SCC肺转移。综合起来，我们假设在Smad 4突变体中减弱TGFβ诱导的免疫抑制和炎性TME， HNSCCs使免疫治疗更有效，因此双重TGFβ/PD-L1抑制可根除这些疾病。 HNSCC通过T细胞依赖性和非依赖性机制。目标1将进行实验使用新型TGFβ/PD-L1抑制剂药物对遗传小鼠模型和移植的人的治疗 HNSCC确定Smad 4丢失和TGFβ1过表达是否预测对TGFβ/PD-L1的治疗反应在免疫活性和受损条件下对HNSCC的双重抑制。目标2将评估T细胞- TGFβ抑制对抗PD-L1介导的SCC增敏或协同作用的依赖性机制根除，利用在目标1和患者HNSCC标本中产生的肿瘤来检查Smad 4丢失和 TGFβ/PD-L1水平与免疫抑制性T细胞特征相关。Aim 3将使用Aim中生成的肿瘤 1，以评估TGFβ/PD-L1抑制的髓样细胞依赖性靶向作用是否有助于治疗在HNSCC和转移中的疗效，以及患者HNSCC标本，以检查Smad 4丢失和TGFβ/PD-L1 水平与髓样细胞和相关分子标记物的增加相关。这些研究将导致新的治疗策略，HNSCC患者的高复发率和转移。另夕h 机制研究将为未来的生物标志物驱动的选择提供新的见解， HNSCC患者中的TGFβ/PD-L1双重抑制。