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，但头部和颈部鳞状细胞癌的5年生存率 （HNSCC）仍保持约50％。 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的“驱动程序”，是FDA批准的代理Cetuximab的目标。 单独的HNSCC患者对西妥昔单抗以及ERBB家族的反应范围广泛。 靶向酪氨酸激酶抑制剂（TKIS），例如Afatinib。重要的是，即使结合化学或 放疗，EGFR抑制剂无法消除100％的肿瘤细胞。这些耐药性肿瘤细胞称为 “残留疾病细胞”已被称为储层，最终从中抗致命的药物癌 出现以驱动进展。在支持方面，治疗诱导的肿瘤收缩程度与 某些癌症中无进展生存。那，加深了HNSCC对靶向药物的反应 预计精确攻击残留疾病状态的药物的基于机理的组合将扩展 无进展和整体生存。 目前，肿瘤细胞持久性和治疗异质性的生物学机制 - 在HNSCC患者中观察到的诱导肿瘤反应不明显，突出了关键的知识差距。我们的 初步数据表明，用靶向EGFR或MEK抑制剂抑制EGFR-MEK-MAPK轴 在人和鼠类HNSCC细胞系中，迅速刺激先天免疫反应，导致诱导 趋化因子和细胞因子向肿瘤微环境（TME）和抗原中的免疫细胞发出信号的趋化因子和细胞因子 演示途径（MHC I类）。重要的是，效应T细胞和NK细胞的可变诱导 在A中观察到化学吸引剂，CXCL10，促肿瘤细胞因子，TGFβ和IL6和MHC I类 HNSCC细胞系的面板，支持以下观念：EGFR/MEK抑制剂内的内在异质性 诱导的先天免疫反应指示直接但可变的免疫细胞参与该治疗 回复。 我们建议用患者标本，同源鼠询问HNSCC残留疾病状态 肿瘤模型和人类HNSCC细胞系作为描述介导的新型旁分泌途径的一种手段 治疗诱导的癌细胞-TME串扰。该建议将检验快速转录的假设 被靶向的EGFR-MEK-MAPK轴抑制剂刺激的重编程会影响抗 - 与免疫微环境通信的促肿瘤趋化因子和细胞因子，领先 直接参与治疗反应。此外，HNSCC患者的内在异质性 在整体反VS中。这种先天反应的亲穆罗基尼平衡有助于观察到的可变性 观察到的响应的程度。成功完成研究可能会突出显示 未来使用基于机制的药物组合进行合理靶向的免疫原理。 AIM 1：表征早期EGFR/MEK抑制剂引起的患者重新编程和免疫剂含量 鼠的原位HNSCC肿瘤，并与治疗反应相关。研究将检验假设 更大程度的治疗反应与效应T细胞浸润的增加有关，并改善 髓样细胞含量以及增加MHC I类表达。目标2：鼠HNSCC细胞系将是 在免疫能力和缺乏的宿主中进行矫ps以矫形为单位，以测试特定的直接贡献 对EGFR和MEK抑制剂治疗反应的免疫细胞群体。目标3：定义机制 EGFR/MEK抑制剂诱导的HNSCC细胞系中的先天免疫反应，并测试在体内的作用 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