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

TGFbeta/PD-L1 在 HNSCC 中的双重抑制机制

• 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
• 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

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) 占重型头颈 (HN) 癌症的 90% 以上。 吸烟者对治疗的反应较差，并且在所有 HNSCC 中复发/复发率最高 FDA 批准程序性死亡 1 (PD-1) 抑制剂用于治疗复发性 HNSCC。 仅对约 25% 的 HNSCC 有效，表明存在额外的免疫抑制/逃避机制。 据报道，转化生长因子-β1（TGFβ1）是一种免疫抑制剂，在超过 60% 的烟草中含量升高。 TGFβ1 是 HNSCC 所特有的，它会引起大多数肿瘤的过度炎症。 浸润白细胞是骨髓细胞，开发有效针对这些细胞的新治疗干预措施。 缺乏具有转移性的 HNSCC 模型阻碍了肿瘤微环境 (TME) 特征 该应用采用新的治疗剂来靶向两者。 PD-L1 和 TGFβ 在 HNSCC 和转移中的作用，并分析了其潜在机制。 小鼠模型中，Smad4（一种在烟草相关 HNSCC 中经常丢失的肿瘤抑制因子）被删除 头颈部上皮细胞中的 (Smad4-/-) Smad4 缺失会导致鳞状细胞癌和转移，以及代偿性 TGFβ1。 初步数据显示，Smad4-/- SCC 也过度表达 PD-L1 和短期 TGFβ。 抑制使 SCC 对抗 PD-L1 敏感。此外，在 SCC 被根除的小鼠中，重新移植相同的 SCC。 细胞系未能引发新的肿瘤，表明存在记忆 T 细胞依赖性的 TGFβ 抗肿瘤反应。 抑制作用还减少了免疫受损小鼠的鳞状细胞癌肺转移。总的来说，我们很挣扎。 减弱 Smad4 突变体中 TGFβ 诱导的免疫抑制和炎症 TME HNSCC 使免疫治疗更加有效，因此双重 TGFβ/PD-L1 抑制可以根除这些 HNSCC 将通过 T 细胞依赖性和非依赖性机制进行实验。 使用新型 TGFβ/PD-L1 抑制剂药物对遗传小鼠模型和移植人类进行治疗 HNSCC 确定 Smad4 缺失和 TGFβ1 过度表达是否可以预测对 TGFβ/PD-L1 的治疗反应 在免疫能力强和受损的条件下对 HNSCC 进行双重抑制，目的 2 将评估 T 细胞。 TGFβ 抑制对致敏或与抗 PD-L1 介导的 SCC 协同作用的依赖机制 根除，利用目标 1 中产生的肿瘤和患者 HNSCC 标本来检查 Smad4 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 中生成的肿瘤。 1 评估 TGFβ/PD-L1 抑制的骨髓细胞依赖性靶向作用是否有助于治疗 HNSCC 和转移的疗效，以及患者 HNSCC 标本检查 Smad4 丢失和 TGFβ/PD-L1 是否存在 水平与增加的骨髓细胞和相关分子标记相关。 针对高复发率和转移率的 HNSCC 患者的新治疗策略。 机制研究将为未来临床试验的生物标志物驱动选择提供新的见解 HNSCC 患者中的 TGFβ/PD-L1 双重抑制。

项目成果

Dual inhibition of TGF-β and PD-L1: a novel approach to cancer treatment.

TGF-β 和 PD-L1 的双重抑制：一种新的癌症治疗方法。

• 发表时间: 2022-06
• 影响因子: 6.6
• 作者: Gulley, James L;Schlom, Jeffrey;Barcellos;Wang, Xiao;Seoane, Joan;Audhuy, Francois;Lan, Yan;Dussault, Isabelle;Moustakas, Aristidis
• 通讯作者: Moustakas, Aristidis

Cancer-Associated Fibroblasts Facilitate Squamous Cell Carcinoma Lung Metastasis in Mice by Providing TGFβ-Mediated Cancer Stem Cell Niche.

癌症相关成纤维细胞通过提供 TGFβ 介导的癌症干细胞利基促进小鼠鳞状细胞癌肺转移。

• 发表时间: 2021
• 作者: Shi, Xueke;Luo, Jingjing;Weigel, Kelsey J;Hall, Spencer C;Du, Danfeng;Wu, Fanglong;Rudolph, Michael C;Zhou, Hongmei;Young, Christian D;Wang, Xiao
• 通讯作者: Wang, Xiao