肿瘤细胞治疗研究
英文原题：Autocrine activity of engineered IL-33 mRNA enhances adoptive T-cell therapy for peritoneal carcinomatosis and synergizes with IL-12 mRNA.
依据：腹膜癌病（PC）仍是一项重大临床挑战，各瘤种的治疗选择均有限。
理论依据：腹膜癌病（PC）仍是多种肿瘤中的重大临床挑战，治疗选择有限。肿瘤特异性T细胞过继细胞治疗（ACT）具有前景，但疗效常受免疫抑制性肿瘤微环境（TME）影响。研究者正在探索腹腔内ACT，以提高其对腹腔内转移灶的疗效。白细胞介素-33（IL-33）属于IL-1家族细胞因子，兼具免疫和炎症双重作用，可能增强抗肿瘤应答。我们评估了IL-33 mRNA工程化T细胞能否提高小鼠PC模型中的ACT疗效，并考察其与IL-12 mRNA的潜在协同作用。 方法：将编码IL-33、IL-12或IL-33突变体的mRNA电转至OT.I、PMEL-1及CEA特异性CAR-T细胞中。体外实验检测细胞因子生成和细胞毒性；通过RNA测序分析IL-33 mRNA电转后的转录组变化。利用ST2缺失T细胞，评估转移T细胞与宿主细胞表面IL-33受体表达的作用。小鼠PC体内模型中，采用ELISA、ELISpot和流式细胞术评估生存和免疫应答。 结果：电转IL-33 mRNA的OT.I T细胞以ST2依赖、T细胞内在的方式增强IFN-γ表达。体内实验中，IL-33工程化T细胞显著改善PC模型的生存。IL-33重塑TME，增加先天淋巴样细胞和嗜酸性粒细胞浸润，同时减少中性粒细胞。使用稳定型IL-33突变体工程化T细胞可进一步增强抗肿瘤活性。将IL-33突变体和IL-12 mRNA共同电转至PMEL-1 T细胞，可协同提高IFN-γ生成、细胞毒性和长期记忆，并带来更好的肿瘤控制和再次攻击保护。在腹膜肿瘤模型中使用经IL-33突变体/IL-12 mRNA电转的CEA CAR-T细胞也证实了这些结果。 结论：IL-33通过自分泌ST2信号促进IFN-γ表达并调节TME，从而增强ACT疗效。IL-33突变体可提高细胞因子稳定性和抗肿瘤活性，与IL-12联合则产生协同效应。这一策略有望增强腹膜癌病的ACT疗效。
Rationale : Peritoneal carcinomatosis (PC) remains a major clinical challenge with limited therapeutic options across tumor types. Adoptive cell therapy (ACT) with tumor-specific T cells offers promise, but its efficacy is often impaired by the immunosuppressive tumor microenvironment (TME). Intraperitoneal ACT is under investigation to improve its effectiveness against metastases within the peritoneal cavity. IL-33, a cytokine of the IL-1 family, plays dual roles in immunity and inflammation and may enhance antitumor responses. We evaluated whether IL-33 mRNA-engineered T cells improve ACT efficacy in murine PC models and assessed potential synergy with IL-12 mRNA. Methods : OT.I, PMEL-1, and CEA-specific CAR T cells were electroporated with mRNA encoding IL-33, IL-12, or an IL-33 mutein. In vitro assays measured cytokine production and cytotoxicity. RNA-seq was performed to analyze transcriptomic changes following IL-33 mRNA electroporation. ST2 -/- T cells were used to evaluate the role of IL-33 receptor expression on transferred T cells versus host cells. In vivo studies in murine PC models assessed survival and immune responses using ELISA, ELISpot, and flow cytometry. Results : IL-33 mRNA-electroporated OT.I T cells exhibited enhanced IFN- expression in a ST2-dependent, T cell-intrinsic manner. In vivo , IL-33-engineered T cells significantly improved survival in PC models. IL-33 reshaped the TME by increasing infiltration of innate lymphoid cells and eosinophils while reducing neutrophils. Engineering T cells with a stabilized IL-33 mutein further enhanced antitumor activity. Co-electroporation of IL-33 mutein and IL-12 mRNA in PMEL-1 T cells led to synergistic increases in IFN- production, cytotoxicity, and long-term memory, resulting in superior tumor control and protection upon rechallenge. These findings were confirmed using IL-33 mutein/IL-12 mRNA-electroporated CEA CAR T cells in peritoneal tumor models. Conclusions : IL-33 enhances ACT efficacy by promoting IFN- expression via autocrine ST2 signaling and by modulating the TME. The IL-33 mutein improves cytokine stability and antitumor activity, while combination with IL-12 yields synergistic effects. This strategy holds promise for enhancing ACT in peritoneal carcinomatosis.
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