Induction of Therapeutic Immunity in the Tumor Microenvironment

肿瘤微环境中治疗性免疫的诱导

• 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
• 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

 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（申请人提供）：越来越多的证据表明，患有各种形式的实体瘤的患者（乳腺癌、结肠癌、肺癌、卵巢癌、肾癌和头颈癌、黑色素瘤等），其中含有非包囊化的、有组织的免疫细胞浸润簇（即称为三级淋巴样结构（TLS）或异位淋巴样器官（ELO））具有显著更好的临床表现（上级总生存期、无进展生存期和/或对化疗的反应性）。值得注意的是，肿瘤相关TLS已被认为是淋巴结T细胞引发的重要位点，并且其特征在于成熟（DC-LAMPhi+）DC沉积物与肿瘤微环境（TME）内的MECA-79+（又名外周淋巴结地址素; PNAd，淋巴结中“高内皮微静脉”/HEV的标志物）血管周围的募集T细胞群密切接触。在野生型和外周淋巴结缺陷受体动物的鼠实体癌模型中也报告了类似的结果。在肺癌患者肺部病变中的TLS中已经鉴定出幼稚淋巴细胞，这使得有可能 这些免疫细胞第一次遇到它们的同源抗原，并在体内在TME内（而不是在外周淋巴结内）发育成抗原特异性T效应细胞。在人类非小细胞肺癌（NSCLC）标本中也发现了TLS，其特征是DC/1型T细胞簇靠近B细胞“巢”，与长期生存率提高相关。NSCLC相关TLS中的B细胞似乎也经历了从幼稚前体细胞正常分化编程的所有阶段，包括体细胞超变和IG类别转换、浆细胞发育和（抗肿瘤）抗体产生。这些数据表明，在适当的条件下，肿瘤可以转化为功能性淋巴样“器官”，其中保护性免疫可以有效地启动。我们的提案将采用信息丰富的野生型、突变型和转基因小鼠模型，以确定Tbet和IL-36/IL-36 R介导的治疗性TLS发展和诱导能够监管播散性疾病的保护性抗肿瘤T细胞的细胞和分子机制，并评估如何通过癌症疫苗进一步增强与肿瘤部位转化为“淋巴器官”相关的治疗益处，过继性细胞疗法（ACT）和免疫检查点阻断（ICB）。