Novel Strategies for Immunotherapy of Cancer

描述（由申请方提供）：MHC I类和II类限制性抗原的鉴定为开发更有效的癌症疫苗提供了机会，然而，目前使用肿瘤抗原的免疫治疗策略相对无效，并且没有产生任何持久治疗益处的令人信服的证据。最近的研究表明，肿瘤部位的炎性Th 17细胞和先天免疫可能促进而不是抑制癌症的发展和进展。此外，肿瘤部位的CD 4+调节性T（Treg）细胞有效地抑制由疫苗接种引起的CD 4+和CD 8 + T细胞应答，从而促进肿瘤生长。这些研究表明，了解免疫细胞和肿瘤细胞之间的相互作用是开发更有效的癌症治疗方法的关键一步。基本原理是炎症是许多类型癌症发病机制的主要驱动力，包括结直肠癌和病毒感染相关的恶性肿瘤。抗肿瘤免疫、炎性CD 4 + Th 17细胞和免疫抑制细胞之间微妙的动态平衡可能是肿瘤消除、发展和进展的重要因素。尽管炎性细胞因子和CD 4 + Th 17细胞在癌症中的重要性，但它们在癌症中的作用和调节机制仍然存在争议。因此，我们假设先天免疫信号传导在炎症控制中至关重要，炎症反过来又调节适应性免疫和CD 4 + Th 17细胞分化。因此，识别控制炎症和Th 17分化的关键先天免疫信号分子对于我们确定炎症和Th 17细胞在炎症相关癌症发展中的作用以及剖析炎性细胞因子和Th 17细胞直接或间接调节肿瘤发展的分子机制至关重要。为了验证我们的中心假设，我们提出了三个目标：1）确定NLRC 5和TAK 1是否可以调节体内关键的促炎细胞因子和Th 17细胞; 2）确定炎性细胞因子和Th 17细胞在癌症发展中的功能; 3）通过操纵先天信号分子，Th 17和Treg细胞来增强抗肿瘤免疫。有利的结果将为通过调节这些炎症和CD 4 + T细胞亚群来治疗癌症和其他免疫疾病开辟新的机会。 公共卫生相关性：免疫疗法是一种很有前途的癌症治疗方法，但目前的策略相对无效，主要是由于对免疫细胞和肿瘤细胞之间相互作用的了解不完全。该项目的目标是了解炎症和Th 17细胞在肿瘤微环境中的作用和机制，这有助于开发更有效的癌症免疫治疗策略。

DESCRIPTION (provided by applicant): Identification of both MHC class I and II restricted antigens has provided opportunities to develop more effective cancer vaccines, however, current immunotherapy strategies with tumor antigens are relatively ineffective and have not produced compelling evidence of any durable therapeutic benefits. Recent studies suggest that inflammatory Th17 cells and innate immunity at tumor sites may promote rather than inhibit cancer development and progression. Moreover, CD4+ regulatory T (Treg) cells at tumor sites potently suppress the CD4+ and CD8+ T-cell responses elicited by vaccination, thus promoting tumor growth. These studies suggest that understanding of the interplay between immune cells and tumor cells is a critical step to develop more effective cancer therapy. The underlying rationale is that inflammation is a major driving force in the pathogenesis of many types of cancer, including colorectal cancer and viral infection-associated malignancies. The delicate and dynamic balance among antitumor immunity, inflammatory CD4+ Th17 cells and immune suppressive cells may be important factor in tumor elimination, development and progression. Despite the importance of inflammatory cytokines and CD4+ Th17 cells in cancer, their role and regulatory mechanisms in cancer remain controversial. We therefore hypothesize that innate immune signaling is critical in the control of inflammation, which in turn modulates adaptive immunity and CD4+ Th17 cell differentiation. Thus, identification of key innate immune signaling molecules that control inflammation and Th17 differentiation will be critical for us to define the role of inflammation and Th17 cells in inflammation-associated cancer development and to dissect molecular mechanisms by which inflammatory cytokines and Th17 cells directly or indirectly modulate tumor development. To test our central hypothesis, we propose three aims: 1) To determine whether NLRC5 and TAK1 can modulate key proinflammatory cytokines and Th17 cells in vivo; 2) To define the function of inflammatory cytokines and Th17 cells in cancer development; 3) To enhance antitumor immunity by manipulating innate signaling molecules, Th17 and Treg cells. A favorable outcome would open new opportunities for treating cancer and other immune diseases through regulating these inflammation and subsets of CD4+ T cells. PUBLIC HEALTH RELEVANCE: Immunotherapy is a promising treatment for cancer patients, but current strategies are relatively ineffective, mainly due to incomplete understanding of knowledge of the interplay between immune cells and tumor cells. The goal of this project is to understand the role and mechanisms of inflammation and Th17 cells in the tumor microenvironment, which aids in developing more effective strategies for cancer immunotherapy.