Targeting tumor desmoplasia to harness cytotoxic immune responses

描述(申请人提供)：细胞毒性淋巴细胞可以通过寻找和杀死恶性细胞来抑制肿瘤的生长。最近对许多不同人类癌症的回顾性研究表明，肿瘤核心内细胞毒性CD8T细胞的存在与更好的预后有关。尽管如此，在大多数癌症中，免疫抑制的肿瘤微环境抑制了肿瘤浸润性淋巴细胞(TIL)溶解其靶标的能力。最近，研究表明，这种免疫抑制不仅由T细胞的功能性瘫痪所介导，而且还由限制TIL与癌细胞接近的物理屏障所介导。这种由肿瘤造成的免疫抑制环境仍然是限制宿主对癌症的免疫力和当前治疗方法成功的主要障碍之一。这项建议的目的是确定胶原纤维如何影响TIL在特定肿瘤间隔中的滞留，并损害其功能潜力。中心假设是，基质通过阻止细胞毒性淋巴细胞穿透富含癌细胞的肿瘤的隔间来抑制抗肿瘤免疫。这一假说是基于成像研究表明T细胞被富含胶原的皮质屏障排除在人类和小鼠肿瘤的核心之外，以及功能研究表明成纤维细胞来源的胶原可以有效地抑制T细胞的激活。这项拟议研究的基本原理是，确定TIL无效的机制有可能转化为新的免疫疗法。已经提出了两个具体的目标来检验这一假说：1)解决肿瘤基质结构在体内肿瘤浸润性CD8 T细胞的区隔和功能中的贡献；2)展示基于纳米颗粒的药物递送系统对肿瘤胶原基质的局部破坏的治疗效果。在第一个目的中，将评估基质基质对TIL定位和激活的影响。将利用药理学和遗传学方法来检查肿瘤基质破坏对TIL区划和效应器分化的影响。在第二个目标中，将评估针对肿瘤基质的新型纳米颗粒制剂在三阴性人乳腺癌小鼠模型中的药代动力学、生物分布、药效学和疗效。这些方法是创新的，利用尖端成像技术和纳米载体来深入表征TIL分区和基质结构之间的关系。这项研究的长期目标是创造治疗癌症的有效免疫疗法。这项拟议的研究意义重大，因为了解TIL如何在肿瘤微环境中失去杀瘤潜力，可以开发干扰免疫抑制机制的下一代癌症治疗方法。释放宿主强大的细胞毒性TIL武器有可能延长和提高癌症患者的生活质量。

DESCRIPTION (provided by applicant): Cytotoxic lymphocytes can inhibit growth of tumors by seeking out and killing malignant cells. Recent retrospective studies across many different human cancers have shown that the presence of cytotoxic CD8 T cells within the tumor core is associated with better prognosis. Still, in most cancers, the immunosuppressive tumor microenvironment inhibits the capacity of tumor infiltrating lymphocytes (TILs) to lyse their targets. Recently, it was shown that such immunosuppression is mediated not only by functional paralysis of T cells but also by physical barriers that limit TIL proximity to cancer cells. This immunosuppressive milieu created by tumors remains one of the principal obstacles limiting host immunity to cancer and success of current therapeutic approaches. The objective in this proposal is to determine how collagen fibers influence retention of TIL in specific tumor compartments and impair their functional potential. The central hypothesis is that stromal matrix restrains anti-tumor immunity by preventing cytotoxic lymphocytes from penetrating compartments of the tumor that are rich in cancer cells. This hypothesis is based on imaging studies demonstrating that T cells are excluded from the core of human and mouse tumors by a collagen-rich cortical barrier and functional studies showing that fibroblast-derived collagen can potently suppress T cell activation. The rationale for the proposed research is that defining mechanisms by which TILs are rendered ineffective has the potential to translate into new immunotherapeutics. Two specific aims have been proposed that will z test the hypothesis: 1) Address the contribution of tumor matrix architecture in the compartmentalization and function of tumor-infiltrating CD8 T cells in vivo; and 2) Demonstrate therapeutic efficacy of a nanoparticle- based drug delivery system for localized disruption of tumor collagen matrix. In the first aim the impact of stromal matrix on localization and activation of TILs will be evaluated. Pharmacologic and genetic approaches will be exploited to examine the consequences of tumor matrix disruption on TIL compartmentalization and effector differentiation. In the second aim pharmacokinetics, biodistribution, pharmacodynamics, and therapeutic efficacy of a novel nanoparticle formulation targeting tumor matrix will be evaluated in a mouse model of triple negative human breast cancer. The approaches are innovative, making use of cutting edge imaging technologies and nanocarriers to enable in depth characterization of the relationship between TIL compartmentalization and matrix architecture. The long-term goal of this research is to create efficacious immunotherapeutics for treatment of cancer. The proposed studies are significant because understanding how TILs lose tumoricidal potential in the tumor microenvironment could enable development of next generation cancer therapies that interfere with immunosuppressive mechanisms. Unleashing the host's powerful armament of cytotoxic TILs has the potential to extend and improve the quality of life for cancer patients.