The Impact of Cancer on the Pathophysiology of Sepsis

癌症对脓毒症病理生理学的影响

• 批准号: 10189636
• 负责人: Craig M Coopersmith
• 金额: $ 29.64万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189636
• 关键词: Animals; Autoimmunity; CD4 Positive T Lymphocytes; Cancer Patient; Cells; Cessation of life; Chemotherapy and/or radiation; Chronic; Data; Disease; Etiology; FOXP3 gene; Functional disorder; Funding; General Population; Global Change; Grant; Hospital Mortality; ITIM; Immune; Immune response; Immunologics; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Infection; Investigation; Knockout Mice; Malignant Neoplasms; Modeling; Molecular; PD-1 blockade; Pathogenicity; Pathologic; Pathway interactions; Patients; Phenotype; Population; Regulatory T-Lymphocyte; Role; Secondary to; Sepsis; Septic Shock; Serum; Signal Transduction; Surface; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Testing; Time; cancer therapy; comorbidity; conditional knockout; cytokine; design; high dimensionality; high risk; immunomodulatory therapies; improved; improved outcome; mortality; mortality risk; novel; prevent; programmed cell death protein 1; receptor; receptor expression; response; septic; septic patients; therapeutic target

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.

概括 恶性肿瘤患者出现败血症的可能性几乎是普通人群的十倍，并且 癌症是化粪池患者最常见的合并症。此外，癌症也是合并症 与败血症中最高的死亡风险相关，并且患者的医院死亡率可能超过50％ 癌症和败血症或化粪池休克。但是，在 与患败血症的健康患者相比，患败血症的癌症患者不好 理解。该建议旨在了解存在的细胞和分子机制 癌症在败血症期间的死亡率增加。我们已经确定并表征了不同的共抑制性 在癌症和败血症的情况下，CD4+ T细胞种群上的受体谱。重要的是，这些 差异在功能上是相关的，因为某些共同抑制性受体阻滞策略具有 与单独的败血症相比，在癌症和败血症的情况下从根本上不同。首先，我们找到了 PD-1封锁无法改善动物败血症期间患有恶性肿瘤的生存率，尽管 该策略仅在败血症中有效。该提案将研究此基础的机制。 接下来，我们发现Tigit封锁可有效防止败血症死亡的动物死亡率 恶性肿瘤，但有趣的是，在以前健康的动物中，败血症无效。这些结果阐明了 事实是，由于存在恶性肿瘤而发生的免疫学变化可能会影响反应能力 进行败血症的免疫疗法，并强调需要设计特定的免疫调节疗法 癌症和败血症患者的反向免疫失调。最后，我们已经确定了一条途径 这可能导致共抑制受体表达和反应性的全球变化 癌症宿主。 IL-27已被证明可以有效调节多个共抑制的表达 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 证明癌症宿主中IL-27的血清浓度有了深远的协同作用 与单独败血症或仅癌症相比，表明高血清IL-27与 在癌症和败血症的情况下增加共抑制信号传导。因此，这是总体假设 建议是，癌症宿主中存在的IL-27水平升高导致T的表达增加 细胞共抑制分子在调节和效应子的CD4+ T细胞的不同子集上，导致 癌症宿主中免疫反应的功能失调和死亡率增加。审讯 该假设将阐明用于控制T细胞共抑制受体的新型免疫治疗途径 癌症宿主的表达并改善死亡率和免疫失调。

项目成果

Defining Ultra-Massive Transfusion through a Systematic Review.

通过系统审查定义超大规模输血。

• DOI: 10.1016/j.amjsurg.2023.09.024
• 发表时间: 2024
• 期刊: American journal of surgery
• 影响因子: 3
• 作者: Meyer,CourtneyH;Bailey,NealMody;Leslie,SharonL;Thrasher,Kenya;Grady,Zach;Sanders,M;Moore,Erica;Nicely,KW;Smith,RandiN
• 通讯作者: Smith,RandiN

Complete response to high-dose IL-2 and enhanced IFNγ+Th17 : TREG ratio in a melanoma patient.

• DOI: 10.1097/cmr.0000000000000283
• 发表时间: 2016-10
• 期刊: Melanoma research
• 影响因子: 2.2
• 作者: Diller ML;Kudchadkar RR;Delman KA;Lawson DH;Ford ML
• 通讯作者: Ford ML

Exogenous IL-2 Induces FoxP3+ Th17 Cells In Vivo in Melanoma Patients.

• DOI: 10.1097/cji.0000000000000139
• 发表时间: 2016
• 期刊: Journal of immunotherapy (Hagerstown, Md. : 1997)
• 作者: Diller ML;Kudchadkar RR;Delman KA;Lawson DH;Ford ML
• 通讯作者: Ford ML