Regulation of Targeted Therapeutic Response by the Immune Microenvironment in HNSCC

HNSCC 免疫微环境对靶向治疗反应的调节

• 批准号: 10477265
• 负责人: LYNN E HEASLEY
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477265
• 关键词: Antibodies; Antigen Presentation Pathway; Biological; CD8-Positive T-Lymphocytes; CXCL10 gene; Cell Line; Cells; Cetuximab; Chemotactic Factors; Clinical; Combined Modality Therapy; Cytokine Signaling; Data; Drug Combinations; Drug Targeting; Drug resistance; EGFR gene; EGFR inhibition; Engineering; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Equilibrium; Exhibits; FDA approved; Family; Future; Genetic Transcription; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Heterogeneity; Human; IL6 gene; Immune; Immune response; Immune signaling; Immunocompetent; Immunofluorescence Immunologic; Immunotherapy; Individual; Inflammatory; Innate Immune Response; Knock-out; Knowledge; Length; Link; MAP Kinase Gene; MEK inhibition; MEKs; MHC Class I Genes; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Mitogen-Activated Protein Kinases; Modeling; Mus; Myeloid Cells; Myeloid-derived suppressor cells; Natural Killer Cells; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Progression-Free Survivals; Radiation therapy; Receptor Protein-Tyrosine Kinases; Regimen; Regulation; Regulatory T-Lymphocyte; Residual Tumors; Role; Signal Transduction; Specimen; Stains; Survival Rate; Testing; Therapeutic; Therapeutic Effect; Time; Tobacco; Transforming Growth Factor beta; Tumor-associated macrophages; Tumor-infiltrating immune cells; Tyrosine Kinase Inhibitor; Veterans; Wild Type Mouse; base; cancer cell; chemokine; cytokine; effector T cell; functional genomics; in vivo; inhibitor; inhibitor therapy; mouse model; neoplastic cell; novel; paracrine; refractory cancer; response; targeted treatment; therapy resistant; transcriptional reprogramming; transcriptome sequencing; treatment response; tumor; tumor microenvironment; tumor-immune system interactions; tumorigenic

Despite optimized therapeutic regimens, the 5-year survival rate for head and neck squamous cell carcinoma (HNSCC) remains around 50%. EGFR is a key component of a receptor tyrosine kinase (RTK) network that functions as a non-mutated “driver” in HNSCC cell lines and is the target for the FDA-approved agent, cetuximab. Individually, HNSCC patients exhibit wide-ranging extent of response to cetuximab as well as ERBB family- targeted tyrosine kinase inhibitors (TKIs) such as afatinib. Importantly, even in combination with chemo- or radiotherapy, EGFR inhibitors fail to eliminate 100% of tumor cells. These therapy-resistant tumor cells, termed “residual disease cells”, have been invoked as a reservoir from which lethal drug resistant cancers ultimately emerge to drive progression. In support, the extent of therapy-induced tumor shrinkage correlates with progression-free survival in some cancers. Thus, deepening the HNSCC response to targeted drugs through mechanism-based combinations of agents that precisely attack the residual disease state is predicted to extend progression-free and overall survival. At present, the biological mechanisms that underlie tumor cell persistence and the heterogeneity of therapy- induced tumor responses observed in HNSCC patients are ill-defined, highlighting a critical knowledge gap. Our preliminary data demonstrate that inhibition of the EGFR-MEK-MAPK axis with targeted EGFR or MEK inhibitors in human and murine HNSCC cell lines rapidly stimulates an innate immune response leading to induction of chemokines and cytokines that signal to immune cells in the tumor microenvironment (TME) as well as antigen presentation pathways (MHC class I). Importantly, variable induction of the effector T cell and NK cell chemoattractant, CXCL10, pro-tumorigenic cytokines, TGFβ and IL6, and MHC class I are observed within a panel of HNSCC cell lines, supporting the idea that intrinsic heterogeneity within this EGFR/MEK inhibitor- induced innate immune response instructs direct, yet variable immune cell participation in the therapeutic response. We propose to interrogate the HNSCC residual disease state with patient specimens, syngeneic murine tumor models and human HNSCC cell lines as a means for delineating novel paracrine pathways mediating therapy-induced cancer cell-TME cross-talk. This proposal will test the hypothesis that rapid transcriptional reprogramming stimulated by targeted EGFR-MEK-MAPK axis inhibitors induces a variable spectrum of anti- and pro-tumorigenic chemokines and cytokines that communicate with the immune microenvironment, leading to its direct participation in the therapeutic response. Moreover, intrinsic heterogeneity among HNSCC patients in the overall anti- vs. pro-tumorigenic balance of this innate response contributes to the observed variability in the extent of the observed responses. Successful completion of the studies may highlight presently unappreciated immune pathways for rational targeting with mechanism-based drug combinations in the future. Aim 1: Characterize early EGFR/MEK inhibitor-induced reprogramming and immune cell content in patient and murine orthotopic HNSCC tumors and associate with therapeutic response. The studies will test the hypothesis that greater degree of therapeutic response is linked to increased effector T cell infiltration and decreased myeloid cell content as well as increased MHC class I expression. Aim 2: Murine HNSCC cell lines will be propagated orthotopically in immune-competent and -deficient hosts to test the direct contributions of specific immune cell populations to the EGFR and MEK inhibitor therapeutic response. Aim 3: Define the mechanism of the EGFR/MEK inhibitor-induced innate immune response in HNSCC cell lines and the test the role in the in vivo therapeutic response.

尽管优化了治疗方案，头颈鳞状细胞癌的 5 年生存率 (HNSCC) 仍占 50% 左右，EGFR 是受体酪氨酸激酶 (RTK) 网络的关键组成部分。 在 HNSCC 细胞系中充当非突变“驱动程序”，并且是 FDA 批准的药物西妥昔单抗的靶标。 就个体而言，HNSCC 患者对西妥昔单抗以及 ERBB 家族表现出广泛的反应程度 - 重要的是，靶向酪氨酸激酶抑制剂（TKI），例如阿法替尼，甚至与化疗或化疗联合使用。 放疗时，EGFR 抑制剂无法 100% 消除肿瘤细胞，这些肿瘤细胞被称为耐药性肿瘤细胞。 “残留的疾病细胞”，已被称为最终致命的耐药癌症的储存库 作为支持，治疗引起的肿瘤缩小程度与相关。 因此，通过加深 HNSCC 对靶向药物的反应。 精确攻击残留疾病状态的基于机制的药物组合预计会延长 无进展生存期和总生存期。 目前，肿瘤细胞持久存在的生物学机制和治疗的异质性 在 HNSCC 患者中观察到的诱导肿瘤反应尚不清楚，这凸显了我们的关键知识差距。 初步数据表明，靶向 EGFR 或 MEK 抑制剂可抑制 EGFR-MEK-MAPK 轴 在人和鼠 HNSCC 细胞系中，快速刺激先天免疫反应，从而诱导 向肿瘤微环境 (TME) 中的免疫细胞以及抗原发出信号的趋化因子和细胞因子 递呈途径（MHC I 类）重要的是，效应 T 细胞和 NK 细胞的诱导可变。 趋化剂、CXCL10、促肿瘤细胞因子、TGFβ 和 IL6 以及 MHC I 类在 HNSCC 细胞系组，支持这种 EGFR/MEK 抑制剂内在异质性的观点 诱导的先天免疫反应指示直接但可变的免疫细胞参与治疗 回复。 我们建议用患者标本、同基因小鼠来询问 HNSCC 残留疾病状态 肿瘤模型和人类 HNSCC 细胞系作为描绘新的旁分泌途径介导的手段 治疗诱导的癌细胞-TME 串扰该提案将检验快速转录的假设。 靶向 EGFR-MEK-MAPK 轴抑制剂刺激的重编程会诱导多种抗- 以及与免疫微环境沟通的促肿瘤趋化因子和细胞因子，导致 此外，HNSCC 患者之间存在内在异质性。 这种先天反应的总体抗肿瘤与促肿瘤发生平衡有助于观察到的变异性 目前观察到的反应的成功完成程度可能会突出。 未来基于机制的药物组合的合理靶向的免疫途径未被重视。 目标 1：表征患者和患者的早期 EGFR/MEK 抑制剂诱导的重编程和免疫细胞含量 小鼠原位 HNSCC 肿瘤及其与治疗反应的相关性这些研究将检验这一假设。 更大程度的治疗反应与效应 T 细胞浸润的增加和 T 细胞浸润的减少有关 骨髓细胞含量以及 I 类 MHC 表达增加 目标 2：鼠 HNSCC 细胞系。 在免疫能力强和免疫缺陷的宿主中原位繁殖，以测试特定的直接贡献 免疫细胞群对 EGFR 和 MEK 抑制剂的治疗反应 目标 3：定义机制。 EGFR/MEK 抑制剂在 HNSCC 细胞系中诱导的先天免疫反应及其在体内的作用测试 治疗反应。

项目成果

Role of epidermal growth factor receptor inhibitor-induced interferon pathway signaling in the head and neck squamous cell carcinoma therapeutic response.

• DOI: 10.1186/s12967-021-02706-8
• 发表时间: 2021-01-23
• 期刊: Journal of translational medicine
• 影响因子: 7.4
• 作者: Korpela SP;Hinz TK;Oweida A;Kim J;Calhoun J;Ferris R;Nemenoff RA;Karam SD;Clambey ET;Heasley LE
• 通讯作者: Heasley LE

Innovations in risk-stratification and treatment of Veterans with oropharynx cancer; roadmap of the 2019 Field Based Meeting.

患有口咽癌的退伍军人的风险分层和治疗方面的创新；

• DOI: 10.1016/j.oraloncology.2019.104440
• 发表时间: 2020
• 期刊: Oral oncology
• 影响因子: 4.8
• 作者: Sandulache,VC;Lei,YL;Heasley,LE;Chang,M;Amos,CI;Sturgis,EM;Graboyes,E;Chiao,EY;Rogus-Pulia,N;Lewis,J;Madabhushi,A;Frederick,MJ;Sabichi,A;Ittmann,M;Yarbrough,WG;Chung,CH;Ferrarotto,R;Mai,Weiyuan;Skinner,HD;Du
• 通讯作者: Du