Complement, anti-tumor immunity and apoptosis-based therapy

描述（申请人提供）：许多传统的癌症治疗方法，如化疗、放疗和免疫治疗，在不同程度上依赖于诱导肿瘤细胞凋亡。细胞凋亡诱导治疗的有效性可以通过肿瘤部位的初始局部炎症反应和随后的特异性免疫反应显着增强。事实上，在啮齿动物模型中，诱导细胞凋亡后的炎症反应已被证明对某些恶性肿瘤的完全消退很重要。补体系统在炎症反应中发挥重要作用，可以调节B细胞和T细胞反应的发展。然而，在细胞凋亡的背景下，天然IgM与补体活化和调理的结合对于凋亡细胞的有效吞噬摄取至关重要，这一过程被认为是限制和解决炎症以及调节免疫的重要过程。我们已经证明，涉及靶向补体抑制的免疫治疗方法改变了放疗后肿瘤环境中的炎症和免疫谱，并在调节肿瘤生长、动物存活和诱导抗肿瘤T细胞反应方面显著提高了治疗效果。我们的目标是了解这种反应的机制，以及开发一种基于靶向补体抑制的新策略来提高放疗的治疗效果。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活化和凋亡细胞的调理，并且在放疗后抑制补体依赖性凋亡细胞摄取将促进坏死，创造增强的免疫刺激环境，调节巨噬细胞和树突状细胞的活化和分化，并增强或触发针对肿瘤的特异性免疫。我们将验证上述假设，并使用体内和体外治疗范例研究IgM特异性和不同补体调理素的作用。

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.