Reviving cancer immune surveillance with CD4 T cell help

利用 CD4 T 细胞恢复癌症免疫监视

基本信息

批准号：
10675117
负责人：
Michael Clavon Brown
金额：
$ 24.86万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-08 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10675117
关键词：
Aftercare Agonist Antibodies Antigen-Presenting Cells Antigens Autologous Bilateral Biological Assay Biometry Brain Brain Neoplasms Breast Melanoma CD14 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cancer Patient Capsid Cell Density Cell physiology Cells Chemosensitization Childhood Clinical Communicable Diseases Complement Cytolysis Data Dendritic Cells Fatty acid glycerol esters Flow Cytometry Gene set enrichment analysis Glioblastoma Glioma Goals Helper-Inducer T-Lymphocyte Human I-antigen Immune Immune response Immune system Immunity Immunization Immunize Immunobiology Immunologic Surveillance Immunotherapy Infiltration Inflammation Inflammatory Injections Ligation Malignant Neoplasms Measures Mediating Memory Mentors Modeling Molecular Target Monitor Mus Myeloid Cell Activation Myeloid Cells Natural Immunity Natural Killer Cells Oncolytic poliovirus PTPRC gene Pathway interactions Patients Pattern recognition receptor Phase Phenotype Play Poliomyelitis Poliovirus Vaccines Poly I-C Principal Component Analysis Public Health Qi RNA analysis Recurrence Research Role Route SILV gene STING agonists Seeds Slice T-Lymphocyte TNFRSF5 gene Testing Tetanus Tetanus Toxoid Tetanus Vaccine Therapeutic Tumor Antigens Tumor Immunity Tumor-associated macrophages Vaccinated Vaccination Vaccines Virotherapy Work adaptive immunity antitumor effect base cancer cell cancer immunotherapy cancer therapy cancer type cell type clinical translation clinically actionable cytokine design differential expression draining lymph node granulocyte immunogenic macrophage melanoma neoplasm immunotherapy neoplastic cell novel novel therapeutics pathogen programs response single cell analysis subcutaneous success targeted cancer therapy transcriptome transcriptome sequencing tumor tumor growth tumor microenvironment

项目摘要

Abstract The immune system is capable of eliminating advanced malignant tumors, yet cancer immunotherapy success has been limited to a subset of cancer types. Conventional CD4, or `helper', T cells play an integral role in orchestrating immune responses, and can potentiate the function of antitumor immunity: both via activation and potentiation of antigen presenting cell function and antitumor CD8 T cells. My postdoctoral work demonstrated that reactivating childhood vaccine-specific CD4 T cells after intratumor injection of recall antigen (e.g. polio capsid or tetanus toxoid), mediates antitumor efficacy and causes both innate and adaptive inflammation within tumors. The antitumor efficacy of intratumor recall responses were partially dependent upon CD8 T cells, and coincided with infiltration of activated granulocytic macrophages with phenotypes distinct from tumor associated macrophages after direct innate stimulation with Poly IC. Thus, inducing CD4 T cell recall represents a novel therapeutic opportunity, with a distinct mode of inflammatory and antitumor potential. We hypothesize that intratumor childhood vaccine-specific CD4+ T cell recall responses instigate distinct and durable inflammatory reprograming of myeloid cells to potentiate antitumor CD8+ T cell function and mediate antitumor efficacy. To test this hypothesis, we will define reprogramming of innate immunity after triggering intratumor recall responses and determine its role in mediating antitumor efficacy (Aim 1) and test if polio vaccine-specific CD4+ T cell recall responses `help' antitumor CD8+ T cells (Aim 2). These analyses will inform clinically actionable routes to develop recall antigen-based therapies that enlist CD4 T cell help within tumors (the goal of the independent, R00 phase). The clinical translation of these findings will be informed by identifying therapeutic strategies, such as combined innate pattern recognition receptor agonist therapy, that may synergize with recall antigens in mediating systemic antitumor efficacy; as well as identifying more targeted molecular routes to recapitulate CD4 T cell help in tumors therapeutically (Aim 3). The K99 phase of this work will be mentored by several distinguished experts in tumor immunobiology and cancer immunotherapy: including Drs. Darell Bigner (primary Mentor, cancer immunotherapy of brain tumors), Simon Gregory (computational expert), Qi Jing-Li (T cell biologist using transcriptome analyses to gauge T cell function), Amy Heimberger (tumor associated myeloid cell expert who has previously applied transcriptome analyses to define activation/suppressive features of tumor associated myeloid cells), and James Herndon II (biostatistical support). This proposal will enable clinical translation of recall antigens to cancer patients and will seed a research program that leverages the potent immune-stimulating effects of CD4+ T cell help to develop novel cancer therapies.

抽象的免疫系统能够消除晚期恶性肿瘤，但癌症免疫疗法成功已限于癌症类型的一部分。常规CD4或“助手”，T细胞在策划免疫反应，并可以增强抗肿瘤免疫力的功能：通过激活和抗原表现出细胞功能和抗肿瘤CD8 T细胞的增强。我的博士后作品证明了在肿瘤内注射召回抗原后，它重新激活儿童疫苗特异性CD4 T细胞（例如脊髓灰质炎衣壳或破伤风毒素），介导抗肿瘤功效，并在内部引起先天和适应性炎症肿瘤。肿瘤内召回反应的抗肿瘤功效部分取决于CD8 T细胞，以及与激活的粒细胞巨噬细胞浸润与肿瘤相关的表型直接先天刺激poly IC后的巨噬细胞。因此，诱导CD4 T细胞回忆代表了一种新颖治疗机会，具有独特的炎症和抗肿瘤潜力。我们假设这一点肿瘤内儿童期疫苗特异性CD4+ T细胞回忆反应引起了不同的耐用炎症重新编程髓样细胞以增强抗肿瘤CD8+ T细胞功能并介导抗肿瘤功效。到检验该假设，我们将在触发肿瘤内召回反应后定义先天免疫的重编程并确定其在介导抗肿瘤功效（AIM 1）中的作用（AIM 1），并测试脊髓灰质炎疫苗特异性CD4+ T细胞回忆反应“帮助”抗肿瘤CD8+ T细胞（AIM 2）。这些分析将为临床可行的途径提供信息回忆基于抗原的疗法，可在肿瘤中吸收CD4 T细胞帮助（独立，R00期的目标）。这些发现的临床翻译将通过确定治疗策略（例如组合）来告知先天模式识别受体激动剂疗法，可能与召回抗原在介导全身性中协同作用抗肿瘤功效；以及识别更多靶向的分子途径以概括CD4 T细胞在肿瘤中有助于治疗（目标3）。这项工作的K99阶段将由肿瘤的几位杰出专家指导免疫生物学和癌症免疫疗法：包括Drs。 Darell Bigner（癌症免疫疗法的主要导师脑肿瘤），西蒙·格雷戈里（Simon Gregory）（计算专家），Qi jing-li（使用转录组分析的T细胞生物学家为了衡量T细胞功能），Amy Heimberger（肿瘤相关的髓样细胞专家，以前已应用转录组分析以定义肿瘤相关髓样细胞的激活/抑制特征）和詹姆斯 Herndon II（生物统计支持）。该提案将使回忆抗原临床翻译为癌症患者并将播种一项研究计划，该计划利用CD4+ T细胞的有效免疫刺激作用有助于开发新型的癌症疗法。