Sulforaphane activates CD8⁺T cells antitumor response through IL-12RB2/MMP3/FasL-induced MDSCs apoptosis’

Abstract

BackgroundExtensive attention has been given to the role of myeloid-derived suppressor cells (MDSCs) in driving tumor progression and treatment failure. Preclinical studies have identified multiple agents that eliminate MDSCs. However, none have been authorized in the cliniccal ues due to the safety reasons. In the present study, we investigated the efficacy and mechanism of sulforaphane (SFN) to eliminate MDSCs in the tumor microenvironment (TME).MethodsWe monitored SFN effect on tumor growth and the percents or apoptosis of immune cell subsets in mice models bearing LLC or B16 cells. Flow cytometry, quantitative reverse transcription-PCR, immunohistochemistry, ELISA, immunofluorescence, imaging flow cytometry and western blot were performed to validate the role of SFN on MDSCs function in vivo and in vitro. RNA sequencing was then used to interrogate the mechanisms of how SFN regulated MDSCs function. Tumor xenograft models were established to evaluate the involvement of IL-12RB2/MMP3/FasL induced MDSCs apoptosis in vivo. We verified the effect of SFN on MDSCs and CD8+T cells in the blood samples from a phase I clinical trial (KY-2021–0350).ResultsIn this study, we elucidated that SFN liberated CD8+T-cell antitumor ability by reducing MDSCs abundance, leading to repressed tumor growth. SFN treatment suppressed MDSCs accumulation in the peripheral blood and tumor sites of mice, but had no effect on the bone marrow. Mechanistically, SFN activates IL-12RB2, which stimulates the MMP3/FasL signaling cascade to trigger caspase 3 cleavage and induce apoptosis in MDSCs. Clinically, SFN treatment eliminates peripheral MDSCs and increases the percentage and activation of CD8+T cells.ConclusionsCollectively, we uncovered the role of SFN in eliminating MDSCs to emancipate CD8+T cells through IL-12RB2/MMP3/FasL induced apoptosis, thus providing a strategy for targeting MDSCs to control tumors and improve clinical efficacy.

Advances in and Perspectives on Transgenic Technology and CRISPR-Cas9 Gene Editing in Broccoli

“…Broccoli’s contribution to weight and fat loss, enhanced metabolism, and strengthened immunity further solidifies its status as a healthful food choice [ 8 , 9 ]. Broccoli is also noted for containing the compound sulforaphane, which inhibits the growth of cancer cells and induces apoptosis in some cancers [ 10 , 11 , 12 , 13 , 14 , 15 ].Recent studies have also highlighted the unique antiplatelet selectivity of sulforaphane, which can reduce thrombus formation and enhance the thrombolytic activity of recombinant tissue plasminogen activator (rtPA), thus exhibiting promise for improved preventive and therapeutic strategies [ 16 ]. Moreover, phenolic compounds extracted from broccoli have shown efficacy in preventing and reducing fatty liver formation [ 17 ].…”