Ongoing inflammation following chemotherapy induces immunosuppression

化疗后持续的炎症会导致免疫抑制

• 批准号: 10093109
• 负责人: Chuanlin Ding
• 金额: $ 27.19万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10093109
• 关键词: Address; Antioxidants; Bone Marrow; Breast Cancer Patient; Breast Cancer cell line; CX3CL1 gene; Cancer Center; Cells; Centers of Research Excellence; Chemotherapy-Oncologic Procedure; Clinical; Clinical Management; Data; Dose; Fluorouracil; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis; Hematopoietic stem cells; Human; Immune response; Immune system; Immunity; Immunocompetence; Immunosuppression; In Vitro; Inflammation; Inflammatory; Intercellular adhesion molecule 1; Investigation; Mitochondria; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Neoplasm Metastasis; Oxidative Phosphorylation; Paclitaxel; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Production; Reactive Oxygen Species; Recruitment Activity; Regimen; Role; Side; Stromal Cells; Testing; Time; Tissues; Tumor Immunity; Tumor-Derived; Tumor-associated macrophages; Up-Regulation; anti-tumor immune response; antitumor effect; base; cancer immunotherapy; cancer therapy; chemokine; chemotherapy; combinatorial; cytokine; design; gemcitabine; in vivo; monocyte; neoplastic cell; novel; novel therapeutic intervention; receptor; response; tumor; tumor immunology; tumor microenvironment; tumor progression

Conventional chemotherapy has been thought to act through the direct killing of tumor cells. However, accumulating evidence indicates that immune competence is crucially required for chemotherapy efficacy. It is expected that loss of this immunity during chemotherapy has a negative effect on its efficacy. Therefore, the impact of chemotherapy on anti-tumor immunity needs further investigation in order to rationally design combinatorial regimens for conventional chemotherapy. In the preliminary studies, we have demonstrated that repeated chemodrug gemcitabine (GEM) treatment promoted the expansion and differentiation of immunosuppressive Ly6Chigh monocytic-MDSC (M-MDSC). Tumor-derived soluble factors, such as GM-CSF and soluble ICAM-1(sICAM-1), were up-regulated upon chemo-drug treatment. In tumor-free naïve mice, GEM treatment induced the immunosuppressive activity of Ly6Chigh myeloid cells in the bone marrow (BM). The chemokine CX3CL1 and its receptor CX3CR1 expression levels were elevated in the BM. Higher levels of mitochondrial reactive oxygen species (mtROS) were also observed in tumor cells and BM stromal cells following chemotherapy. Furthermore, chemotherapy induced NF-κB activation leading to the hyperproduction of GM-CSF by tumor cells. Based on these preliminary data, we hypothesize that chemotherapy enhances the production of mtROS in tumor cells and BM stromal cells, which increases the expressions of GM-CSF and sICAM-1 as well as CX3CL1 leading to the enhanced immunosuppression of M-MDSC in the TME. These hypotheses will be addressed by two Specific Aims. Aim 1 defines the roles of GM-CSF and sICAM-1 in chemotherapy-induced differentiation of immunosuppressive Ly6Chigh myeloid cells and the mechanisms underlying mtROS and upregulation of GM-CSF and sICAM-1 in tumor cells; Aim 2 determines the mechanisms by which host cell- derived chemokine CX3CL1 regulates the accumulation and immunosuppressive function of inflammatory Ly6Chigh myeloid cells in the BM. The findings from these studies will allow us to gain a better understanding the underlying mechanisms by which ongoing inflammation following multi-dose clinical regimens of chemotherapy modulates anti-tumor immunity, and rationally design a novel therapeutic approach by combining chemotherapy with mitochondria-targeted antioxidants for cancer treatment.

传统化疗被认为是通过直接杀死肿瘤细胞来发挥作用。然而， 越来越多的证据表明，免疫能力对于化疗效果至关重要。这是 预计化疗过程中这种免疫力的丧失会对其疗效产生负面影响。因此， 化疗对抗肿瘤免疫的影响需要进一步研究才能合理设计 常规化疗的组合方案。在初步研究中，我们已经证明 重复化疗药物吉西他滨（GEM）治疗促进了细胞的扩增和分化 免疫抑制性 Ly6Chigh 单核细胞 MDSC (M-MDSC)。肿瘤来源的可溶性因子，例如 GM-CSF 和 可溶性 ICAM-1 (sICAM-1) 在化疗药物治疗后上调。在无肿瘤幼鼠中，GEM 治疗诱导骨髓 (BM) 中 Ly6Chigh 骨髓细胞的免疫抑制活性。这 BM 中趋化因子 CX3CL1 及其受体 CX3CR1 表达水平升高。更高水平的 在肿瘤细胞和骨髓基质细胞中也观察到线粒体活性氧（mtROS） 化疗。此外，化疗诱导 NF-κB 激活，导致 GM-CSF 过度产生 由肿瘤细胞。根据这些初步数据，我们假设化疗可以增强 肿瘤细胞和骨髓基质细胞中的 mtROS，也增加了 GM-CSF 和 sICAM-1 的表达 CX3CL1 导致 TME 中 M-MDSC 的免疫抑制增强。这些假设将 通过两个具体目标来解决。目标 1 定义了 GM-CSF 和 sICAM-1 在化疗引起的 免疫抑制性 Ly6Chigh 骨髓细胞的分化及其 mtROS 和机制 肿瘤细胞中 GM-CSF 和 sICAM-1 的上调；目标 2 确定宿主细胞的机制 衍生趋化因子CX3CL1调节炎症的积累和免疫抑制功能 BM 中的 Ly6Chigh 骨髓细胞。这些研究的结果将使我们能够更好地了解 多剂量临床化疗方案后持续炎症的潜在机制 调节抗肿瘤免疫，合理设计联合化疗的新治疗方案 与线粒体靶向抗氧化剂一起用于癌症治疗。