Renal cancer-derived exosomes induce tumor immune tolerance by MDSCs-mediated antigen-specific immunosuppression

Abstract

Backgound: Although Myeloid-derived suppressor cells (MDSCs) have a prominent ability to suppress the immune responses of T lymphocytes and propel tumor immune escape, a lack of profound systemic immunesuppression in tumor-bearing mice and tumor patients. The underlying mechanism of these remains unclear. Methods: For this purpose, renal cancer-derived exosomes (RDEs) were first labeled with PKH67 and been observed the internalization by MDSCs. Flow cytometry analysis showed the proportion and activity change of MDSCs in spleen and bone marrow induced by RDEs. Further, western blot experiments were used to verify triggered mechanism of MDSCs by RDEs. Finally, proliferation and cytotoxicity of cytotoxic T lymphocytes (CTLs) cocultured with MDSCs in vitro and a series of experiments in vivo were performed to demonstrate the specific inhibitory effect of RDEs-induced MDSCs. Results: This study suggested that RDEs crucially contributed to presenting antigenic information, activating and driving specific immunosuppressive effect to MDSCs. HSP70, which is highly expressed in RDEs, initiate this process in a toll like receptor 2 (TLR2)-dependent manner. Importantly, RDEs-induced MDSCs could exert an antigen-specific immunosuppression effect on CTL and specific promote renal tumors-growth and immune escape in consequence. Conclusion: The immunosuppression mediated by MDSCs which is induced by RDEs is antigen-specific. HSP70, which is highly expressed in RDEs, plays a pivotal role in this process. Targeted abrogating the function of MDSCs, or eliminating the expression of HSP70 in exosomes, or blocking the crosstalk between them provides a new direction and theoretical support for future immunotherapy.

Deciphering Repertoire of B16 Melanoma Reactive TCRs by Immunization, In Vitro Restimulation and Sequencing of IFNγ-Secreting T Cells

“…In particular, we found that, after a heat shock and in the presence of microparticles, the tumor lysate has immunosuppressive activity that declines within 2 days. This is in agreement with other studies that demonstrated the immunosuppressive activity of tumor-derived exosomes [ 30 , 31 , 32 ].…”

Exosomes as mediators of immune regulation and immunotherapy in cancer

“…Likewise, renal cancer cell‐derived exosomes harboring HSP70 promoted MDSC proliferation and activation through engagement of TLR2 signaling. Notably, the MDSCs primed by the renal cancer cell‐derived exosomes enhanced renal tumor growth and promoted immunosuppression [144]. Exosomes released from breast cancer cells supported the expansion of early‐stage MDSCs (eMDSCs) through the transfer of miR‐9 and miR‐181a.…”

Current status of research on exosomes in general, and for the diagnosis and treatment of kidney cancer in particular

“…The establishment of pre-metastatic ecological niche is a complex process that involves the binding of exosomes secreted by cancer cells to the stromal cells of target organs, leading to the reprogramming of target cells, activation of signalling pathways and ultimately the establishment of a pre-metastatic microenvironment in target organs, thus providing the prerequisite for tumour metastasis [ 69 , 70 ]. Exosomes are considered the main mediators of cell–cell interactions in the tumour microenvironment and are involved in promoting tumour cell invasion, angiogenesis and immunosuppression [ 71 – 75 ]. The role of exosomal constituents in kidney cancer are shown in Fig.…”

“…Myeloid-derived suppressor cells (MDSCs) exert potent inhibitory effects on several immune cells, and their high concentration aggregation in the tumour microenvironment is one of the reasons for the formation of tumour immune escape [ 87 , 88 ]. It was found that Hsp70 was abundantly present in exosomes secreted by mouse kidney cancer cells (Renca cells), upregulated the expression of arginase 1 (ARG-1), iNOS, interleukin 6 (IL-6) and VEGF and induced the expression of MDSCs by phosphorylating STAT3 (p-STAT3) pathway, thus promoting tumour growth [ 75 , 89 ].…”