Novel Strategies for Immunotherapy of Cancer

描述(由申请人提供)：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，目前的肿瘤抗原免疫治疗策略相对无效，尚未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Th17细胞和先天免疫可能促进而不是抑制癌症的发生和发展。此外，肿瘤部位的CD4+调节性T细胞(Treg)可以有效地抑制疫苗接种引起的CD4+和CD8+T细胞反应，从而促进肿瘤的生长。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。其基本原理是，炎症是许多类型癌症发病的主要驱动力，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CD4+Th17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、发展和发展的重要因素。尽管炎性细胞因子和CD4+Th17细胞在癌症中的重要性，但它们在癌症中的作用和调控机制仍然存在争议。因此，我们假设先天免疫信号在控制炎症中至关重要，而炎症反过来又调节获得性免疫和CD4+Th17细胞分化。因此，识别控制炎症和Th17分化的关键先天免疫信号分子对于我们确定炎症和Th17细胞在炎症相关肿瘤发展中的作用以及剖析炎症细胞因子和Th17细胞直接或间接调控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NLRC5和TAK1是否可以在体内调节关键的促炎细胞因子和Th17细胞；2)确定炎症细胞因子和Th17细胞在癌症发展中的作用；3)通过操纵先天信号分子Th17和Treg细胞来增强抗肿瘤免疫。一个有利的结果将为通过调节这些炎症和CD4+T细胞亚群来治疗癌症和其他免疫疾病打开新的机会。

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.