肿瘤细胞治疗研究
英文原题：Dual targeting OX40 and IL-2 receptor enhances antitumor activity through tumor-infiltrating Treg depletion and CD8(+) T-cell proliferation.
我们的研究揭示了一种新的 IL-2 设计方法，可解决现有策略的若干关键缺陷，并阐明了 aOX40-mIL2-Fc 疗法的细胞机制。
背景：调节性T细胞（Treg）强抑制活性和细胞毒性T淋巴细胞（CTL）功能障碍，是有效抗肿瘤免疫的主要障碍，晚期癌症中尤其如此。已有多种抗OX40（aOX40）激动性抗体，但抗肿瘤疗效有限。白细胞介素-2（IL-2）可扩增CTL，但有严重副作用。 方法：我们通过Fab空间位阻阻断及减弱IL-2活性的N88D突变（R替代）构建了aOX40-mIL2-Fc双特异性抗体。作为比较，还使用293F表达系统制备aOX40-Fc和IL-2/aOX40-Fc。利用单细胞分析和流式细胞术检测肿瘤微环境（TME）中T细胞亚群变化。通过小鼠肿瘤模型，以肿瘤生长和生存评估aOX40-mIL2-Fc抗肿瘤疗效，并以体重减轻、炎症性细胞因子产生和外周血NK细胞增殖评估毒性。荷瘤小鼠随机分组，各组肿瘤平均大小相近。 结果：aOX40-mIL2-Fc双特异性抗体-细胞因子融合物产生协同治疗效果且毒性有限，疗效优于IL-2-Fc或单独aOX40治疗，并能使肿瘤对再次攻击产生抵抗。从细胞机制看，aOX40-mIL2-Fc治疗显著清除Treg，并增加TME中干样及效应功能性的终末CD8+ T细胞，同时避免外周NK细胞扩增。此外，该双特异性抗体显著增强抗程序性死亡配体1（PD-L1）治疗效果。 结论：本研究提出一种新型IL-2设计方法，解决现有策略若干关键缺点，并阐明aOX40-mIL2-Fc疗法的细胞机制。同时，aOX40-mIL2-Fc联合PD-L1阻断是一种战略性治疗方法，可协同增强肿瘤控制并克服免疫检查点阻断耐药。
BACKGROUND: The strong regulatory T cell (Treg) inhibitory activity and dysfunctional cytotoxic T lymphocytes (CTLs) represent major barriers to effective antitumor immunity, particularly in late-stage cancer. Multiple anti-OX40 (aOX40) agonistic antibodies have been developed but exhibit limited antitumor efficacy. Interleukin-2 (IL-2) effectivity expands CTLs but has severe side effects. METHODS: We construct an aOX40-mIL2-Fc bispecific antibody through Fab physical blocking and attenuated IL-2 with R reducing N88D mutation. We also produced aOX40-Fc and IL-2/aOX40-Fc as a comparison using the 293F expression system. Single-cell and flow cytometry were used to analyze the change of T-cell subsets in the tumor microenvironment (TME). Mouse tumor models were used to assess the antitumor efficacy of aOX40-mIL2-Fc by tumor growth and survival, and toxicity by body weight loss, inflammatory cytokine production, and natural killer (NK) cell proliferation in the blood. The tumor-bearing mice were randomly assigned, and the average size was similar among various groups. RESULTS: aOX40-mIL2-Fc bispecific antibody-cytokine exhibited a synergistic therapeutic effect with limited toxicity, outperforming IL-2-Fc or aOX40 alone treatment, and conferring resistance to tumor rechallenge. On cellular mechanisms, aOX40-mIL2-Fc treatment showed great Treg depletion and increased both stem-like and effector functional terminal CD8 + T cells in the TME, while avoiding NK cells expansion in the periphery. Furthermore, this bispecific antibody remarkably improved the anti-programmed death-ligand 1 (PD-L1) therapeutic effect. CONCLUSIONS: Our study unveils a novel approach to IL-2 design that addresses several critical shortcomings of existing strategies and elucidates the cellular mechanisms underlying aOX40-mIL2-Fc therapy. Meanwhile, combining aOX40-mIL2-Fc with PD-L1 blockade represents a strategic approach to enhance tumor control and overcome resistance to immune checkpoint blockade therapies synergistically.
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