The Impact of Cancer on the Pathophysiology of Sepsis

摘要 恶性肿瘤患者患脓毒症的可能性是普通人群的近十倍， 在败血症患者中，癌症是最常见的并存疾病。此外，癌症也是共同发病的。 与脓毒症死亡风险最高有关，在患有以下疾病的患者中，住院死亡率可超过50% 癌症和败血症或败血症休克。然而，死亡率上升背后的原因是 患脓毒症的癌症患者与患脓毒症的健康患者相比不太好。 明白了。这项提议旨在了解细胞和分子机制，通过这些机制 癌症会增加脓毒症期间的死亡率。我们已经确定并表征了不同的协同抑制 癌症和脓毒症背景下的CD4+T细胞群上的受体图谱。重要的是，这些 差异在功能上是相关的，因为一些共抑制受体阻断策略 与单纯的脓毒症相比，在设置癌症和脓毒症方面的疗效是根本不同的。首先，我们发现 PD-1的阻断未能改善已有恶性肿瘤的动物在脓毒症期间的存活率 这一策略仅对脓毒症有效。这项提案将对其背后的机制进行调查。 接下来，我们发现TIGIT阻滞剂在预防已有败血症的动物中的死亡率方面是有效的。 恶性，但有趣的是，对以前健康的动物的脓毒症无效。这些结果说明了 由于先前存在的恶性肿瘤而发生的免疫学变化会影响反应性的事实 对脓毒症的免疫治疗，并强调需要设计特定的免疫调节疗法来 逆转癌症和脓毒症患者的免疫失调。最后，我们确定了一条路径 这可能是共抑制受体表达和反应性发生全球变化的原因 癌症败血症宿主。已有研究表明，IL-27可有效调节多种共抑制因子的表达 在癌症和自身免疫模型中T细胞表面的受体。我们的初步数据 显示癌症脓毒症宿主血清IL-27浓度的显著协同增加 与单独的脓毒症或单独的癌症相比，表明高血清IL-27与 在癌症和脓毒症的环境中增加共抑制信号。因此，这一最重要的假设 有观点认为，癌症脓毒症宿主体内IL-27水平的升高会导致T细胞表达的增加 CD4+T细胞不同亚群上的细胞共抑制分子，包括调节性和效应性，导致 癌症败血症宿主免疫反应的功能失调和死亡率增加。审问 这一假说将阐明控制T细胞共抑制受体的新免疫治疗途径 表达并改善癌症败血症宿主的死亡率和免疫失调。

Summary Patients with malignancy are nearly ten times more likely to develop sepsis than the general population, and cancer represents the most common co-morbidity in septic patients. Moreover, cancer is also the co-morbidity associated with the highest risk of death in sepsis, and hospital mortality can exceed 50% in patients with cancer and either sepsis or septic shock. However, the etiology behind the increased mortality seen in cancer patients who develop sepsis compared to healthy patients who develop sepsis is not well understood. This proposal aims to understand the cellular and molecular mechanisms by which the presence of cancer increases mortality during sepsis. We have identified and characterized distinct coinhibitory receptor profiles on CD4+ T cell populations in the setting of cancer and sepsis. Importantly, these differences are functionally relevant because some coinhibitory receptor blockade strategies have fundamentally different efficacy in the setting of cancer and sepsis compared to sepsis alone. First, we found that PD-1 blockade fails to improve survival during sepsis in animals with pre-existing malignancy even though this strategy is effective in sepsis alone. The mechanisms underlying this will be investigated in this proposal. Next, we found that TIGIT blockade is effective in preventing mortality from sepsis in animals with pre-existing malignancy, but interestingly is ineffective in sepsis in previously healthy animals. These results illuminate the fact that immunologic changes occurring as a result of pre-existing malignancy can impact the responsiveness to immunotherapy for sepsis, and highlight the need to design specific immunomodulatory therapies to reverse immune dysregulation in patients with cancer and sepsis. Finally, we have identified a pathway that may be responsible for the global changes in coinhibitory receptor expression and responsiveness in cancer septic hosts. IL-27 has been shown to potently regulate the expression of multiple coinhibitory receptors on the surface of T cells in models of both cancer and autoimmunity. Our preliminary data demonstrate a profound synergistic increase in serum concentrations of IL-27 in cancer septic hosts as compared to either sepsis alone or cancer alone, demonstrating that high serum IL-27 is associated with increased coinhibitory signaling in the setting of cancer and sepsis. Thus, the overarching hypothesis of this proposal is that increased levels of IL-27 present in cancer septic hosts results in the increased expression of T cell coinhibitory molecules on distinct subsets of CD4+ T cells, both regulatory and effector, that results in functional dysregulation of immune responses and increased mortality in cancer septic hosts. Interrogation of this hypothesis will elucidate novel immunotherapeutic pathways to control T cell coinhibitory receptor expression and improve mortality and immune dysregulation in cancer septic hosts.