肿瘤细胞治疗研究
英文原题：IgG2a-formatted 4-1BB agonism combined with S100A9 inhibition enhances T cell activation and tumor control in a preclinical model of multiple myeloma.
这些发现确立了4-1BB激动剂的同种型特异性疗效，并支持将4-1BB刺激与TQ联合作为增强MM持久免疫治疗应答的有前景策略。
免疫疗法已成为多发性骨髓瘤（MM）的一种有前景的治疗策略，但由于免疫抑制性骨髓（BM）微环境（以T细胞功能障碍和免疫抑制性髓系细胞积聚为特征），复发仍然频繁。共刺激受体4-1BB（CD137，TNFRSF9）可增强T细胞和NK细胞的效应功能，但其在MM中的治疗用途尚未充分确立。Tasquinimod（TQ）是一种临床阶段的S100A9抑制剂，通过限制抑制性髓系细胞的募集和活性提供了一种互补方法。
采用单细胞RNA测序和流式细胞术，评估了MM小鼠疾病进展期间以及新诊断MM患者中的4-1BB表达。在5TGM1荷瘤小鼠中评估治疗潜力，分别使用两种4-1BB激动剂LOB12.3（IgG1）和3H3（IgG2a）治疗，并设同型对照。随后将先导激动剂与TQ联合，以研究对免疫抑制性肿瘤微环境的双重靶向。通过BM和脾浆细胞增多及血清M蛋白水平量化肿瘤负荷。采用多参数流式细胞术分析免疫调节。采用Mann-Whitney U检验或单因素ANOVA确定统计学显著性（p < 0.05）。
4-1BB 在 T 细胞和 NK 细胞上的表达在小鼠肿瘤发展过程中逐渐增加。在原发性 MM 患者 BM 样本中，使用 urelumab 进行离体 4-1BB 刺激增强了效应反应，增加了 IFN- + 和 Granzyme B + CD3 + T 细胞，同时伴有 CD56 + NK 细胞增加和 IFN- + NK 细胞活性升高的趋势。在体内，4-1BB 激动剂治疗促进了 T 细胞亚群扩增，并具有克隆特异性效应：IgG2a 克隆 3H3 显著降低了 M 蛋白水平和 BM 浆细胞增多，而 IgG1 克隆 LOB12.3 诱导了 NK 细胞耗竭并表现出有限的抗肿瘤活性。将 3H3 与 TQ 联合可提供更优的抗骨髓瘤疗效，使 BM 浆细胞增多从对照组的 62.5% 降至联合治疗下的 14.1%。从机制上看，该联合治疗增强了 Granzyme B 表达、效应 T 细胞分化和树突状细胞成熟（CD86 上调），共同克服了 BM 免疫抑制。
BACKGROUND: Immunotherapy has emerged as a promising strategy for multiple myeloma (MM), yet relapse remains frequent due to the immunosuppressive bone marrow (BM) microenvironment, characterized by T cell dysfunction and accumulation of immunosuppressive myeloid cells. The co-stimulatory receptor 4-1BB (CD137, TNFRSF9) can enhance T and NK cell effector functions, but its therapeutic utility in MM is not well established. Tasquinimod (TQ), a clinical-stage S100A9 inhibitor, offers a complementary approach by limiting the recruitment and activity of suppressive myeloid cells. METHODS: 4-1BB expression was assessed during disease progression in MM mice and in newly diagnosed MM patients using single-cell RNA sequencing and flow cytometry. Therapeutic potential was evaluated in 5TGM1 tumor-bearing mice treated with two 4-1BB agonists, LOB12.3 (IgG1 ) and 3H3 (IgG2a), using isotype controls. The lead agonist was subsequently combined with TQ to investigate dual targeting of the immunosuppressive tumor microenvironment. Tumor burden was quantified via BM and spleen plasmacytosis and serum M-protein levels. Immune modulation was analyzed using multi-parameter flow cytometry. Statistical significance was determined using the Mann-Whitney U test or one-way ANOVA (p < 0.05). RESULTS: 4-1BB expression progressively increased on T and NK cells during tumor development in mice. In primary MM patient BM samples, ex vivo 4-1BB stimulation with urelumab enhanced effector responses, increasing IFN- + and Granzyme B + CD3 + T cells, alongside trends toward increased CD56 + NK cells and elevated IFN- + NK cell activity. In vivo, 4-1BB agonist treatment promoted expansion of T cell subsets, with clone-specific effects: the IgG2a clone 3H3 significantly reduced M-protein levels and BM plasmacytosis, whereas the IgG1 clone LOB12.3 induced NK cell depletion and demonstrated limited anti-tumor activity. Combining 3H3 with TQ provided superior anti-myeloma efficacy, reducing BM plasmacytosis from 62.5% in controls to 14.1% under combination treatment. Mechanistically, the combination enhanced Granzyme B expression, effector T cell differentiation, and dendritic cell maturation (CD86 upregulation), collectively overcoming BM immunosuppression. CONCLUSIONS: These findings establish the isotype-specific efficacy of 4-1BB agonists and support 4-1BB stimulation combined with TQ as a promising strategy to enhance durable immunotherapeutic responses in MM.
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