Melanoma-derived small extracellular vesicles remodel the systemic onco-immunity via disrupting hematopoietic stem cell proliferation and differentiation

• Published in: Cancer letters 2022-10, Vol.545, p.215841-215841, Article 215841
• Main Authors: Du, Zhimin, Feng, Yueyuan, Zhang, Hui, Liu, Jinbao, Wang, Jinheng
• Format: Article
• Language: English
• Subjects: Antibodies; Bone marrow; Cancer; CD4 antigen; CD8 antigen; Cell cycle; Cell differentiation; Cell proliferation; Cytometry; Exosomes; Extracellular vesicles; Hematopoietic dysregulation; Hematopoietic stem cells; Immune checkpoint; Immune system; Immunity (Disease); Immunomodulation; Immunoregulation; Immunotherapy; Intracellular; Laboratory animals; Lymph nodes; Lymphatic system; Lymphocytes T; Mass cytometry; Melanoma; Metastasis; Myeloid-derived suppressor cells; Natural killer cells; PD-1 protein; PD-L1 protein; Progenitor cells; Proteins; Software; Spleen; Suppressor cells; Systemic immune landscape; Tumor microenvironment; Tumors
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2022.215841

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. •Tumor sEVs influenced the composition and intracellular pathways of immune cells.•Tumor sEVs enhanced the PD-1/PD-L1 axis in CD4 T cells and myeloid cell subsets.•Tumor sEVs promoted the differentiation of hematopoietic stem cells towards MDSCs.•Tumor sEVs directly promoted the survival and activation of MDSCs.