Du Zhimin, Feng Yueyuan, Zhang Hui, Liu Jinbao, Wang Jinheng
Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, China; Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China; School of Nursing, Guangzhou Medical University, Guangzhou, 510182, China.
Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, China; Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
Cancer Lett. 2022 Oct 1;545:215841. doi: 10.1016/j.canlet.2022.215841. Epub 2022 Jul 31.
Hematopoiesis and the immune system beyond the tumor microenvironment are typically dysregulated in cancer. Tumor-derived small extracellular vesicles (sEVs) containing exosomes are emerging contributors to tumor progression and immunomodulation. However, a comprehensive definition of how tumor-derived sEVs impacts systemic immunity is lacking. In this study, we used mass cytometry with extensive antibody panels to determine the expression of 24 immune cell markers, eight intracellular proteins, and seven immune checkpoint proteins in systemic immune cell lineages. The systemic immune landscape in response to tumor-derived sEVs across three immune organs in a melanoma mouse model was then characterized. Melanoma-derived sEVs significantly and extensively influenced the composition and intracellular pathways of immune lineage and T cells. An immunosuppressive immune system with decreased natural killer and CD8 T cells in the spleen and bone marrow (BM), increased regulatory T cells in lymph nodes, and increased polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in the BM, was induced by melanoma-derived sEVs. Additionally, melanoma-derived sEVs significantly enhanced the PD-1/PD-L1 axis in CD4 T cells and myeloid cell subsets. These sEVs largely promoted the proliferation of multiple hematopoietic stem and progenitor cell subsets and accelerated their differentiation towards MDSCs in naive mice and mice undergoing hematopoietic reconstruction. Moreover, melanoma-derived sEVs directly promoted the survival and activation of MDSCs in vitro. Collectively, our work examines the effects of tumor-derived sEVs on the systemic onco-immune macroenvironments and highlights the contribution of these sEVs to the dysregulation of hematopoiesis and systemic immune landscape in cancer.
肿瘤微环境之外的造血和免疫系统在癌症中通常会失调。包含外泌体的肿瘤衍生小细胞外囊泡（sEVs）正成为肿瘤进展和免疫调节的促成因素。然而，目前缺乏关于肿瘤衍生sEVs如何影响全身免疫的全面定义。在本研究中，我们使用带有大量抗体组合的质谱流式细胞术来确定全身免疫细胞谱系中24种免疫细胞标志物、8种细胞内蛋白和7种免疫检查点蛋白的表达。然后对黑色素瘤小鼠模型中三个免疫器官对肿瘤衍生sEVs的全身免疫格局进行了表征。黑色素瘤衍生的sEVs显著且广泛地影响了免疫谱系和T细胞的组成及细胞内信号通路。黑色素瘤衍生的sEVs诱导了一种免疫抑制性免疫系统，脾脏和骨髓（BM）中的自然杀伤细胞和CD8 T细胞减少，淋巴结中的调节性T细胞增加，BM中的多形核骨髓来源抑制细胞（PMN-MDSC）增加。此外，黑色素瘤衍生的sEVs显著增强了CD4 T细胞和髓系细胞亚群中的PD-1/PD-L1轴。这些sEVs在很大程度上促进了多种造血干细胞和祖细胞亚群的增殖，并加速了它们在未致敏小鼠和接受造血重建的小鼠中向MDSCs的分化。此外，黑色素瘤衍生的sEVs在体外直接促进了MDSCs的存活和激活。总的来说，我们的工作研究了肿瘤衍生sEVs对全身肿瘤免疫宏观环境的影响，并强调了这些sEVs对癌症中造血失调和全身免疫格局的作用。
