Ongoing inflammation following chemotherapy induces immunosuppression

传统的化疗被认为是通过直接杀死肿瘤细胞来起作用的。然而， 越来越多的证据表明，免疫能力是化疗效果所必需的。它是 预计化疗期间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有待进一步研究才能合理设计 常规化疗的联合方案。在初步研究中，我们已经证明 吉西他滨(GEM)反复化疗促进肿瘤细胞的扩增和分化 免疫抑制Ly6鸡单核细胞-MDSC(M-MDSC)。肿瘤衍生的可溶性因子，如GM-CSF和 化疗后可溶性细胞间黏附分子-1(sICAM-1)表达上调。在没有肿瘤的幼稚小鼠中，GEM 治疗可诱导骨髓中Ly6Chigh髓系细胞的免疫抑制活性。这个 趋化因子CX3CL1及其受体CX3CR1在骨髓中的表达水平升高。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物种(MtROS)。 化疗。此外，化疗诱导了NF-κB的激活，导致GM-CSF高表达 通过肿瘤细胞。根据这些初步数据，我们假设化疗能增强人血清白蛋白的生成 MtROS在肿瘤细胞和骨髓基质细胞中的表达，并增加GM-CSF和sICAM-1的表达 CX3CL1导致TME中M-MDSC免疫抑制增强。这些假设将是 有两个具体的目标。目的1明确GM-CSF和sICAM-1在化疗诱导中的作用 免疫抑制Ly6Chigh髓系细胞的分化及其机制的研究 肿瘤细胞中GM-CSF和sICAM-1的上调；目的2决定宿主细胞- 趋化因子CX3CL1对炎性细胞的聚集和免疫抑制作用的调节 Ly6骨髓中的Chigh髓系细胞。这些研究的结果将使我们更好地了解 多剂量临床方案化疗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治疗新途径 以线粒体为靶点的抗氧化剂用于癌症治疗。

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.