Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Department of Medical Record Management and Statistics, Shandong Provincial, Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, China.
J Immunother Cancer. 2024 Jan 31;12(1):e007983. doi: 10.1136/jitc-2023-007983.
Extensive 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).
We 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).
In 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.
Collectively, 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.
髓系来源抑制细胞（MDSCs）在推动肿瘤进展和治疗失败方面的作用受到了广泛关注。临床前研究已经确定了多种消除 MDSCs 的药物。然而，由于安全性原因，这些药物都没有在临床上得到授权。在本研究中，我们研究了萝卜硫素（SFN）在肿瘤微环境（TME）中消除 MDSCs 的功效和机制。
我们监测了 SFN 对携带 LLC 或 B16 细胞的小鼠模型中肿瘤生长和免疫细胞亚群凋亡百分比的影响。流式细胞术、定量逆转录-PCR、免疫组织化学、ELISA、免疫荧光、成像流式细胞术和 Western blot 用于验证 SFN 在体内和体外对 MDSCs 功能的作用。然后，进行 RNA 测序以探究 SFN 调节 MDSCs 功能的机制。建立肿瘤异种移植模型以评估 IL-12RB2/MMP3/FasL 诱导的 MDSCs 凋亡在体内的参与情况。我们验证了 SFN 在 I 期临床试验（KY-2021-0350）中对 MDSCs 和 CD8 T 细胞的影响。
在这项研究中，我们阐明了 SFN 通过减少 MDSCs 的丰度来释放 CD8 T 细胞的抗肿瘤能力，从而抑制肿瘤生长。SFN 治疗抑制了小鼠外周血和肿瘤部位 MDSCs 的积累，但对骨髓无影响。在机制上，SFN 激活了 IL-12RB2，从而刺激 MMP3/FasL 信号级联反应，导致 caspase 3 切割并诱导 MDSCs 凋亡。临床上，SFN 治疗消除了外周 MDSCs 并增加了 CD8 T 细胞的百分比和激活。
总的来说，我们揭示了 SFN 通过 IL-12RB2/MMP3/FasL 诱导的凋亡消除 MDSCs 以释放 CD8 T 细胞的作用，从而为靶向 MDSCs 控制肿瘤和提高临床疗效提供了一种策略。
