肿瘤细胞治疗研究
英文原题：Targeting epigenetic regulation and post-translational modification with 5-Aza-2' deoxycytidine and SUMO E1 inhibition augments T-cell receptor therapy.
将T细胞疗法与TAK981和5-Aza-2'脱氧胞苷联合使用可能是朝着改善临床结局迈出的重要一步。
利用修饰T细胞的细胞免疫疗法为癌症治疗提供了新途径。CD8 T细胞的T细胞受体（TCR）工程使这些细胞能够识别肿瘤相关抗原和肿瘤特异性新抗原。通过提高效力和体内持久性来改善TCR T细胞疗法对临床成功至关重要。
我们评估了一种新型药物组合，以增强TCR疗法在急性髓系白血病（AML）和多发性骨髓瘤（MM）小鼠模型中的效果。
将 TCR 疗法与 SUMO E1 抑制剂 TAK981 和 DNA 甲基化抑制剂 5-Aza-2' 脱氧胞苷联合使用，在两种已建立的 AML 和 MM 体内肿瘤模型中产生了持久而强效的抗肿瘤活性。我们发现，该药物组合引起了强烈的 T 细胞增殖，增强了 T 细胞中的细胞因子信号传导，改善了 T 细胞的持久性，并减少向耗竭表型的分化。同时，该药物组合通过增加 HLA 和共刺激分子，并令人惊讶地降低抑制性配体表达，增强了肿瘤的免疫原性。
BACKGROUND: Cellular immunotherapy using modified T cells offers new avenues for cancer treatment. T-cell receptor (TCR) engineering of CD8 T cells enables these cells to recognize tumor-associated antigens and tumor-specific neoantigens. Improving TCR T-cell therapy through increased potency and in vivo persistence will be critical for clinical success. METHODS: We evaluated a novel drug combination to enhance TCR therapy in mouse models for acute myeloid leukemia (AML) and multiple myeloma (MM). RESULTS: Combining TCR therapy with the SUMO E1 inhibitor TAK981 and the DNA methylation inhibitor 5-Aza-2' deoxycytidine resulted in strong antitumor activity in a persistent manner against two in vivo tumor models of established AML and MM. We uncovered that the drug combination caused strong T-cell proliferation, increased cytokine signaling in T cells, improved persistence of T cells, and reduced differentiation towards exhausted phenotype. Simultaneously the drug combination enhanced immunogenicity of the tumor by increasing HLA and co-stimulation and surprisingly reducing inhibitory ligand expression. CONCLUSION: Combining T-cell therapy with TAK981 and 5-Aza-2' deoxycytidine may be an important step towards improved clinical outcome.
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