Inducing Immunogenic Cell Death In Cancer

 描述(申请人提供)：每天都有数百亿个细胞被细胞凋亡从我们的体内清除。这些细胞不会引起免疫反应；事实上，细胞凋亡通常被认为是免疫耐受性的。许多癌症疗法寻求在肿瘤细胞中引发凋亡性死亡；其中一类药物针对的是细胞 表面“死亡受体”(DRS)。然而，最近，我们和其他人已经证明，在某些情况下，DR结扎可以引发另一种形式的细胞死亡，称为“坏死性下垂”。坏死性下垂在机制和形态上不同于细胞凋亡；虽然对坏死性下垂的免疫后果知之甚少，但我们的初步数据表明，死于坏死性下垂的细胞会触发炎症和免疫反应。对坏死下垂的描述是一种程序性细胞死亡，也是一种免疫原性，这导致了我们的中心假设：在肿瘤中诱导坏死性下垂将促进有益的抗肿瘤免疫反应，当肿瘤细胞通过凋亡死亡时，这种免疫反应被阻止。我们将通过两个具体的问题来测试这一想法：1。通过坏死性下垂杀死已建立的肿瘤的效果是什么？2.坏死性下垂能促进肿瘤免疫吗？为了解决这些问题，我们开发了新的系统，允许我们使用一种无毒的、细胞渗透的药物在体内快速和同步地触发细胞凋亡或坏死性下垂。我们将使用这个新的系统来直接评估通过不同的细胞死亡程序杀死肿瘤的免疫后果。这项工作代表了第一次评估如果通过炎性程序性细胞死亡来杀死肿瘤的效果，因此有可能确定新的和有益的治疗靶点。

 DESCRIPTION (provided by applicant): Tens of billions of cells are uneventfully eliminated from our bodies by apoptotic cell death each day. These cells do not elicit an immune response; indeed, apoptosis is generally considered to be immunologically tolerogenic. Many cancer therapies seek to trigger apoptotic death in tumor cells; one class of these drugs targets the cell surface "Death Receptors" (DRs). Recently however, we and others have demonstrated that under some conditions DR ligation can trigger another form of cell death termed "necroptosis." Necroptosis is mechanistically and morphologically distinct from apoptosis; while the immune consequences of necroptosis are poorly understood, our preliminary data indicate that cells dying by necroptosis trigger inflammatory and immune responses. The description of necroptosis as a form of programmed cell death that is also immunogenic leads to our central hypothesis: That induction of necroptosis in tumors will promote beneficial anti-tumor immune responses that are prevented when tumor cells die by apoptosis. We will test this idea by pursuing two specific questions: 1. what is the effect of killing established tumors by necroptosis? And, 2. Can necroptosis promote tumor immunity? To address these questions, we have developed novel systems that allow us to rapidly and synchronously trigger either apoptosis or necroptosis in vivo using a non-toxic, cell permeable drug. We will use this novel system to directly assess the immune consequences of killing tumors via distinct cell death programs. This work represents the first assessment of the effects if killing tumors by inflammatory programmed cell death, and as such has the potential to identify novel and beneficial therapeutic targets.