Induction of Therapeutic Immunity in the Tumor Microenvironment

 描述(由申请人提供)：越来越多的证据表明，不同形式的实体肿瘤(乳癌、结肠癌、肺癌、卵巢癌、肾癌和头颈癌、黑色素瘤等)患者的临床预后(总体存活率、无进展存活率和/或化疗反应)明显好于没有此类浸润物的可比患者。值得注意的是，肿瘤相关的TLS被认为是结外T细胞启动的重要部位，其特征是成熟的(DC-LAMPhi+)DC沉积与肿瘤微环境(TME)内MECA-79+(又名外周节点地址；PNAD，淋巴中的高内皮微静脉/HEV的标志)血管周围的招募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小鼠实体癌模型中也报道了类似的结果。在肺癌患者肺部病变的TLS中发现了幼稚的淋巴细胞，这可能是 这些免疫细胞第一次遇到它们的同源抗原，并在体内TME(而不是外周淋巴结)内发育为抗原特异性T效应细胞。在人类非小细胞肺癌(NSCLC)标本中也发现了以B细胞“巢”附近的DC/Type-1 T细胞团为特征的TLS，这与改善长期存活率有关。NSCLC相关TLS中的B细胞似乎也经历了从幼稚前体开始的正常分化程序的所有阶段，包括体细胞过度突变和Ig类转换、浆细胞的发育和(抗肿瘤)抗体的产生。这些数据表明，在适当的条件下，肿瘤可能会转化为功能性的淋巴“器官”，在其中可以有效地启动保护性免疫。我们的计划将使用提供信息的野生型、突变和转基因小鼠模型来确定Tbet和IL-36/IL-36R介导的治疗性TLS开发和诱导能够监督播散性疾病的保护性抗肿瘤T细胞的细胞和分子机制，并评估癌症疫苗、过继细胞疗法(ACT)和免疫检查点阻断(ICB)如何进一步增强与肿瘤部位转变为“淋巴器官”相关的治疗效益。

 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).