Complement, anti-tumor immunity and apoptosis-based therapy

描述（由申请人提供）：许多癌症的常规疗法，如化学疗法、放射疗法和免疫疗法，在不同程度上依赖于诱导肿瘤细胞凋亡。肿瘤部位最初的局部炎症反应和随后的特异性免疫反应可以显着增强细胞凋亡诱导治疗的有效性。事实上，在啮齿动物模型中，诱导细胞凋亡后的炎症反应对于某些恶性肿瘤的完全消退是重要的。补体系统在炎症反应中起重要作用，并且可以调节B和T细胞应答的发展。然而，在细胞凋亡的背景下，天然IgM的结合和补体激活和调理作用对于凋亡细胞的有效吞噬摄取是关键的，这是一个被认为对于限制和解决炎症以及调节免疫力很重要的过程。我们已经表明，涉及靶向补体抑制的免疫抑制方法改变了放射治疗后肿瘤环境中的炎症和免疫特征，并在调节肿瘤生长、动物存活和诱导抗肿瘤T细胞应答方面显著增强了治疗结果。我们的目标是了解参与这种反应的机制，以及开发一种新的策略，以提高基于靶向补体抑制的放疗的治疗效果。我们假设自身反应性IgM与凋亡肿瘤细胞的结合参与了补体激活和凋亡细胞的调理作用，并且在放射治疗后抑制补体依赖性凋亡细胞摄取将促进坏死，产生增强的免疫刺激环境，调节巨噬细胞和树突状细胞的激活和分化，并增强或触发针对肿瘤的特异性免疫。我们将测试上述假设，并研究IgM特异性和不同的补体调理素的作用，使用在体内和体外的治疗范例。

DESCRIPTION (provided by applicant): Many conventional therapies of cancer, such as chemotherapy, radiotherapy and immunotherapy, depend to varying extents on the induction of tumor cell apoptosis. The effectiveness of apoptosis-inducing therapy can be significantly enhanced by an initial local inflammatory reaction at the tumor site and a subsequent specific immune response. Indeed, an inflammatory reaction following the induction of apoptosis has been shown to be important for the complete regression of some malignancies in rodent models. The complement system plays an important role in the inflammatory reaction and can modulate the development of both B and T cell responses. However, in the context of apoptosis, binding of natural IgM and complement activation and opsonization is critical for effective phagocytic uptake of apoptotic cells, a process considered important for limiting and resolving inflammation and for modulating immunity. We have shown that an immunotherapeutic approach involving targeted complement inhibition changes the inflammatory and immune profile within the tumor environment following radiotherapy, and significantly enhances therapeutic outcome in terms of modulating tumor growth, animal survival and induction of an anti-tumor T cell response. Our objective is to understand the mechanisms involved in this response, as well as to develop a novel strategy to enhance the therapeutic outcome of radiotherapy based on targeted complement inhibition. We hypothesize that the binding of self-reactive IgM to apoptotic tumor cells is involved in complement activation and opsonization of apoptotic cells, and that inhibiting complement-dependent apoptotic cell uptake after radiotherapy will promote necrosis, create an enhanced immuno-stimulatory environment, modulate macrophage and dendritic cell activation and differentiation, and augment or trigger specific immunity against a tumor. We will test the above hypothesis and investigate the role of IgM specificity and different complement opsonins using in vivo and in vitro therapeutic paradigms.