SI-2

In multiple myeloma (MM), bone marrow stromal cells (BMSC) shape a unique niche within the bone marrow, promoting T-cell dysfunction and driving MM progression; however, the precise underlying mechanisms remain elusive. Here, we show that BMSC-mediated reprogramming of MM cells led to heightened production of CXCL10. CXCL10 orchestrated the recruitment of γδ T cells into the bone marrow, and this was observed in both the Vk*MYC and 5TGM1 mouse models of MM, as well as in patients experiencing refractory or relapsed MM. Furthermore, the dysfunctional γδ T cells in the MM bone marrow niche exhibited increased PD-1 expression and IL17 production. In the Vk*MYC mouse model, MM-associated bone lesions and mortality were markedly alleviated in Tcrd-/- mice, and MM disease progression could be rescued in these mice upon transplantation of γδ T cells expanded from wild-type mice, but not from Il17-/- mice. Mechanistically, the hypoxic microenvironment prevailing in the MM bone marrow niche stimulated the expression of steroid receptor coactivator 3 (SRC-3) in γδ T cells, which in turn interacted with the transcriptional factor RORγt, promoting Il17 transcription. Pharmacologic inhibition of SRC-3 utilizing SI-2 effectively suppressed Il17A expression in γδ T cells, leading to alleviation of MM progression in the murine models and enhancing the anti-multiple myeloma efficacy of bortezomib. Our results illuminated the bone marrow microenvironment's involvement in provoking γδ T-cell dysfunction throughout MM progression and suggest SRC-3 inhibition as a promising strategy to enhance the effectiveness of immunotherapies targeting γδ T cells.

The As sequestration by iron plaque and the As translocation in rice significantly affect the As accumulation in brown rice, and silicon (Si) application inhibits the As accumulation in rice plants. However, little information is available concerning the effect of Si application on As sequestration by iron plaque and translocation in rice. In this study, a pot experiment using As-contaminated paddy soil with different Si supply levels was conducted to investigate the effects of Si application on the As sequestration by iron plaque on the root surface and the As translocation from different tissues to brown rice. The results showed that the Si2 (0.66 g·kg^-1) treatment significantly increased the activities of CAT (1.81 times), SOD (7.98 times), and POD (1.25 times) in the roots, increased the DCB-extractable Fe concentration (44.35%), and promoted the roughness of iron plaque (108.91%), resulting in a significant increase in the DCB-extractable As concentration of iron plaque (88.32%). Moreover, the Si2 treatment significantly promoted the As accumulation in the roots and inhibited the As translocation from the roots and leaves to the brown rice, leading to a significant decrease in the brown rice As concentration (53.12%). The increase in As sequestration by iron plaque with Si application was attributed to the enhancement of iron plaque formation and the promotion of surface roughness of iron plaque, whereas the inhibition of As translocation from the roots and leaves to the brown rice in the Si application treatment was closely related to the competition between Si with As for transporters and the promotion of As-thiol complex formation and As compartmentalization in vacuolar. These findings provide more insight into the mechanisms of As translocation in rice and will be helpful for exploring strategies to reduce rice grain As through Si supply in As-contaminated paddy fields in South China.