Exosomes from heat‐stressed tumour cells inhibit tumour growth by converting regulatory T cells to Th17 cells via IL‐6

Abstract

Exosomes derived from heat-stressed tumour cells (HS-TEXs), which contain abundant heat shock protein (HSP) 70, strongly induce antitumour immune responses. HSP70-induced interleukin (IL)-6 promotes IL-17 expression and causes rejection of established prostate tumours. However, it remains unclear whether HS-TEXs exhibit antitumour effects by converting regulatory T cells (T ) into T helper type 17 (Th17) cells. In this study, we found that compared with TEXs, HS-TEXs were more potent in stimulating secretion of IL-6 from dendritic cells. In vitro, IL-6 blocked tumour cell-derived transforming growth factor beta 1-induced T differentiation and promoted Th17 cell differentiation. HS-TEXs exerted strong antitumour effects, converting T into Th17 cells with high efficiency, a process that was entirely dependent upon IL-6. Neutralization of IL-17 completely abolished the antitumour effect of TEXs, but only partially inhibited that of HS-TEXs. In addition, we found higher levels of IL-6 and IL-17 in serum from tumour patients treated with hyperthermia, and an increase in Th17 cells and a decrease in T was detected in peripheral blood mononuclear cells isolated from these patients after hyperthermia. Therefore, our results demonstrate that HS-TEXs possess a powerful capacity to convert immunosuppressive T into Th17 cells via IL-6, which contributes to their potent antitumour effect.

Hyperthermia Targeting the Tumor Microenvironment Facilitates Immune Checkpoint Inhibitors

“…Besides, preclinical studies have shown the potential of hyperthermia to promote Th1-related immunity and repress the function of Treg cells. Last, the correcting of dysfunctional CD4 T cell by hyperthermia has also been proven by that patients with tumor treated with hyperthermia showed increases in Th17 cells and decreases in Tregs in the peripheral blood (76).…”

“…In addition, hyperthermia induces M1 macrophages to secrete CXCL10 and IL-6 to induce CD4 T cell differentiation into Th1 and CD4 CTL cells, and reduce MDSC aggregation (57). Moreover, IL-6 stimulated by HS-TEX promotes Treg transformation to Th17 cells and induces CD4 T and CD8 T cell-dependent immune responses (76). Though IL-6 also drives tumor growth and promotes survival of neoplastic cells, these tumor-promoting activities are completely counteracted by the effect of T lymphocyte infiltration into the tumor site with a result of tumor cell killing and tumor regression (81,83).…”

“…Whereas, intra-tumoral injection of HS-TEX derived from colon cancer cells and B lymphoma with hyperthermia efficiently induced tumor-specific anti-tumor immunity in mouse models (89,90). Besides, HS-TEX can activate DCs to release IL-6 to trigger subsequent transformation of the immune microenvironment to reduce Tregs and promote the chemotaxis of T cells to tumors (76). Contents in the HS-TEX plays an important role for its function in TME.…”

Recirculating IL-1R2+ Tregs fine-tune intrathymic Treg development under inflammatory conditions

“…Yet, IL-1R2 expression could not be upregulated on TGF-β-induced Tregs generated in vitro39 , supporting our observation that, under steady-state conditions, the majority of IL-1R2 + Foxp3 + Tregs from secondary lymphoid organs have a thymic origin according to their Helios and Nrp-1 expression. Surprisingly, we could detect only very small subsets of IL-1R2 + cells among Klrg1 + ST2 + Foxp3 + Tregs from different tissues, although several studies had previously reported Il1r2 mRNA expression on tissue-infiltrating Tregs, such as in various tumours and healthy tissues[40][41][42][43][44] . Yet, the highest frequency of IL-1R2 + Tregs was found in the thymus and was enriched among recirculating Tregs, suggesting that IL-1R2 + Tregs are preferentially recruited from secondary lymphoid organs or peripheral tissues back to the thymus.…”

A Challenge to Aging Society by microRNA in Extracellular Vesicles: microRNA in Extracellular Vesicles as Promising Biomarkers and Novel Therapeutic Targets in Multiple Myeloma

“…Although tumor-derived EVs can escape immune surveillance, they can also trigger the cancer immune response [ 43 ]. EVs from heat-stressed tumor cells, which contain Hsp70, inhibit tumor growth by converting regulatory T cells to T helper 17 cells via Interleukin-6 (IL-6) [ 44 ]. EVs derived from a myeloid leukemia cell line, which is carrying cytokines, such as IL-15 and IL-18, activate NK cells and promote their cytotoxicity and proliferation [ 45 ].…”