Human γδ T cells induce CD8+ T cell antitumor responses via antigen-presenting effect through HSP90-MyD88-mediated activation of JNK

Abstract

Human Vγ9Vδ2 T cells have attracted considerable attention as novel alternative antigen-presenting cells (APCs) with the potential to replace dendritic cells in antitumor immunotherapy owing to their high proliferative capacity and low cost. However, the utility of γδ T cells as APCs to induce CD8+ T cell-mediated antitumor immune response, as well as the mechanism by which they perform APC functions, remains unexplored. In this study, we found that activated Vγ9Vδ2 T cells were capable of inducing robust CD8+ T cell responses in osteosarcoma cells. Activated γδ T cells also effectively suppressed osteosarcoma growth by priming CD8+ T cells in xenograft animal models. Mechanistically, we further revealed that activated γδ T cells exhibited increased HSP90 production, which fed back to upregulate MyD88, followed by JNK activation and a subsequent improvement in CCL5 secretion, leading to enhanced CD8+ T cell cross-priming. Thus, our study suggests that Vγ9Vδ2 T cells represent a promising alternative APC for the development of γδ T cell-based tumor immunotherapy.

Identification of immune-related tumor antigens and immune subtypes in osteosarcoma

“…Based on our analysis and research results, we speculated that IS1 subtype might exhibit an immune “hot” phenotype, associated with active immune cells, while IS2 subtype might represent an immune “cold” phenotype, characterized by fewer active immune cells. In the immune “hot” IS1 phenotype, there might be more anti-tumor immune cells, such as CD56 bright natural killer cells, central memory CD8 + T cells, and gamma-delta T cells, which typically exert a positive effect against tumor growth [ [41] , [42] , [43] ]. Conversely, the immune “cold” IS2 phenotype might be more inclined to contain immune cells that promote tumor development, such as Th17 cells [ 44 ].…”

Multi-omic validation of the cuproptosis-sphingolipid metabolism network: modulating the immune landscape in osteosarcoma

“…However, no significant differences were observed in the macrophage infiltration levels between the high-risk and low-risk groups, indicating that macrophage seems to influence limited in the progression of osteosarcoma. Notably, CD8 T cells, crucial for effective recognition and killing of tumor cells during the immune response ( 73 , 74 ), were observed to have lower infiltration levels in high-risk osteosarcoma patients compared to those at low risk ( Figure 8D ). This suggests that the sphingolipid-cuproptosis metabolic network participates in the recruitment of CD8 T cells.…”

Advancements in osteosarcoma management: integrating immune microenvironment insights with immunotherapeutic strategies

“…et al, 2019 ). Wang et al discovered that Vγ9Vδ2 T cell activation enhanced the ability of CD8 + T cells to counter osteosarcoma, with CD8 + T cells managing osteosarcoma progression through the direct elimination of tumor cells ( Wang S. et al, 2023 ). Wang et al also observed that elevated PLOD2 expression in osteosarcoma was associated with enhanced CD8 + T cell infiltration, with such infiltration contributing positively to tumor suppression ( Wang Z. et al, 2022 ).…”

“…Treatments based on γδ T cells and NK cells also showed therapeutic potential. Wang et al’s findings indicated that human Vγ9Vδ2 T cells, as antigen-presenting cells, hold potential in osteosarcoma treatment; their activation increased CCL5 secretion through the upregulation of HSP90 production, MyD88, and JNK activation, effectively enhancing CD8 + T cell responses against osteosarcoma cells ( Wang S. et al, 2023 ). A further study indicated that decitabine, a demethylating agent, amplified the expression of NKG2D ligands including MICB and ULBP1 on osteosarcoma cell surfaces, thus rendering them more susceptible to γδ T cell attack.…”