Induction of Therapeutic Immunity in the Tumor Microenvironment

肿瘤微环境中治疗性免疫的诱导

基本信息

批准号：
9079574
负责人：
Walter J. Storkus
金额：
$ 34.17万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-04 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9079574
关键词：
Agonist Animals Antigens Area Autoimmune Process B-Lymphocytes Biological Markers Blood Vessels Breast CCL19 gene CCL21 gene CXCL13 gene Cancer Model Cancer Patient Cancer Vaccines Cell Therapy Cells Characteristics Clinic Clinical Clinical Treatment Colon Data Dendritic Cells Deposition Development Disease Effector Cell Event Evolution Extranodal Family member Gene-Modified Head and Neck Squamous Cell Carcinoma High Endothelial Venule Hour Human Immune Immunity Immunization Immunoglobulin Class Switching Immunoglobulin Somatic Hypermutation Immunotherapy Infiltration Inflammatory Injection of therapeutic agent Interleukin-1 Interruption Intervention Kidney Lesion Light Lung Lymphocyte Lymphoid Malignant Neoplasms Malignant neoplasm of lung Mediating Modeling Molecular Mus Natural Killer Cells Non-Small-Cell Lung Carcinoma Organ Ovarian PNAd Pathogenesis Patients Peripheral Police Population Process Production Progression-Free Survivals Protocols documentation Psoriasis Recruitment Activity Reporting Signal Transduction Site Solid Solid Neoplasm Specimen Staging Structure T cell therapy T-Lymphocyte Therapeutic Therapeutic Agents Time Tissues Transgenic Mice Translating Treatment Efficacy Tumor Antibodies Tumor Immunity Up-Regulation Vascular Endothelial Cell base chemokine chemotherapy cytokine improved in vivo lymph nodes melanoma mouse model mutant novel outcome forecast plasma cell development programs public health relevance tumor tumor microenvironment vaccine-induced immunity

项目摘要

DESCRIPTION (provided by applicant): Growing evidence suggests that patients with diverse forms of solid tumors (breast, colon, lung, ovarian, renal and head-and-neck carcinoma, melanoma, among others) that contain non-encapsulated, organized clusters of immune cell infiltrates (i.e. termed tertiary lymphoid structures (TLS) or ectopic lymphoid organs (ELO)) have significantly better clinical prognoses (superior overall survival, progression-free survival and/o responsiveness to chemotherapy) than comparable patients that lack such infiltrates. Notably, tumor-associated TLS have been suggested to serve as important sites of extranodal T cell priming, and to be characterized by mature (DC-LAMPhi+) DC deposits in intimate contact with recruited T cell populations around MECA-79+ (aka peripheral node addressin; PNAd, a marker of "high endothelial venules"/HEV in lymph nodes) blood vessels within the tumor microenvironment (TME). Similar results have been reported in murine solid cancer models in both wild-type and peripheral lymph node-deficient recipient animals. Naïve lymphocytes have been identified in TLS within pulmonary lesions of patients with lung cancer, making it likely that these immune cells encounter their cognate antigen for the first time and develop into antigen-specific T effector cells within the TME (rather than in peripheral lymph nodes) in vivo. TLS featuring DC/Type-1 T cell clusters proximal to B cell "nests" have also been identified in human non-small-cell lung cancer (NSCLC) specimens, in association with improved long-term survival. B cells in NSCLC-associated TLS also appear to undergo all stages of their normal differentiation programming from naïve precursors, including somatic hypermutation and Ig class-switching, development of plasma cells and production of (anti-tumor) antibodies. These data suggest the hypothesis that at under the appropriate conditions, tumors may be converted into functional lymphoid "organs" in which protective immunity may be effectively primed. Our proposal will employ informative wild-type, mutant and transgenic mouse models to determine the cellular and molecular mechanisms underlying Tbet- and IL-36/IL-36R-mediated therapeutic TLS development and induction of protective anti-tumor T cells capable of policing disseminated disease, and evaluate how the therapeutic benefits associated with the conversion of tumor sites into "lymphoid organs" can be further enhanced by cancer vaccines, adoptive cell therapies (ACT) and immune checkpoint blockade (ICB).

描述（申请人证明）：越来越多的证据表明，具有多种形式的实体瘤和头颈癌，黑色素瘤，水獭），表明含有无粘贴的，有组织的免疫细胞浸润的簇（即称为的第三纪淋巴样结构（TLS））尤其是，已经提出，已经建议与肿瘤相关的TLS使用肿瘤相关的TLs，以服务于外义tT细胞启动的部位，并且要成为肿瘤相关的TLS，或者是与化学疗法相比，异位淋巴机器人器官（ELO）（ELO）具有明显更好的临床S（总体生存率，无进度的生存率和/O/O的反应率），并且要供应。以与MeCA-79+的招募的T细胞流行在密切接触中的特征（又称外围节点pnad，lymph nodes中的“高内皮静脉静脉息肉”的标志是带有肿瘤微环境（TME）的标志野生型和周围淋巴结定量受体动物的鼠类固体癌模型。免疫细胞在体内（而不是（而不是）在体内（而不是（而不是）外周淋巴结），则在体内（而不是（而不是）在体内（而不是），tls也已鉴定在B细胞中的dc/type-1 T细胞簇中。人类非小细胞肺癌（NSCLC）标本与长期生存相关联，似乎也经历了其正常区分程序的所有阶段细胞和（抗肿瘤）的抗体的产生。确定TBET和IL-36/IL-36R介导的治疗性TLS发育的细胞和分子chanism和IL-36/IL-36/IL-36R介导的TLS发育以及能够与肿瘤位点转化为S的保护肿瘤T细胞的指示。收养细胞疗法（ACT）和免疫检查点阻滞（ICB）。