Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia.
VCU Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia.
Cancer Res. 2021 May 1;81(9):2429-2441. doi: 10.1158/0008-5472.CAN-20-2604. Epub 2021 Mar 16.
Antigen-specific immunotherapy can be limited by induced tumor immunoediting (e.g., antigen loss) or through failure to recognize antigen-negative tumor clones. Melanoma differentiation-associated gene-7/IL24 (MDA-7/IL24) has profound tumor-specific cytotoxic effects in a broad spectrum of cancers. Here we report the enhanced therapeutic impact of genetically engineering mouse tumor-reactive or antigen-specific T cells to produce human MDA-7/IL24. While mock-transduced T cells only killed antigen-expressing tumor cells, MDA-7/IL24-producing T cells destroyed both antigen-positive and negative cancer targets. MDA-7/IL24-expressing T cells were superior to their mock-engineered counterparts in suppressing mouse prostate cancer and melanoma growth as well as metastasis. This enhanced antitumor potency correlated with increased tumor infiltration and expansion of antigen-specific T cells as well as induction of a Th1-skewed immunostimulatory tumor environment. MDA-7/IL24-potentiated T-cell expansion was dependent on T-cell-intrinsic STAT3 signaling. Finally, MDA-7/IL24-modified T-cell therapy significantly inhibited progression of spontaneous prostate cancers in Hi-Myc transgenic mice. Taken together, arming T cells with tumoricidal and immune-potentiating MDA-7/IL24 confers new capabilities of eradicating antigen-negative cancer cell clones and improving T-cell expansion within tumors. This promising approach may be used to optimize cellular immunotherapy for treating heterogeneous solid cancers and provides a mechanism for inhibiting tumor escape. SIGNIFICANCE: This research describes a novel strategy to overcome the antigenic heterogeneity of solid cancers and prevent tumor escape by engineering T lymphocytes to produce a broad-spectrum tumoricidal agent.
抗原特异性免疫疗法可能会受到诱导的肿瘤免疫编辑（例如抗原丢失）的限制，或者由于未能识别抗原阴性的肿瘤克隆而受到限制。黑色素瘤分化相关基因-7/IL24（MDA-7/IL24）在广泛的癌症中具有深远的肿瘤特异性细胞毒性作用。在这里，我们报告了通过基因工程使鼠肿瘤反应性或抗原特异性 T 细胞产生人 MDA-7/IL24，从而增强治疗效果。虽然模拟转导的 T 细胞只能杀死表达抗原的肿瘤细胞，但 MDA-7/IL24 产生的 T 细胞可以破坏抗原阳性和阴性的癌症靶标。与模拟工程化的对应物相比，MDA-7/IL24 表达的 T 细胞在抑制小鼠前列腺癌和黑色素瘤生长以及转移方面更具优势。这种增强的抗肿瘤效力与增加的肿瘤浸润和抗原特异性 T 细胞的扩张以及诱导 Th1 偏向的免疫刺激性肿瘤环境相关。MDA-7/IL24 增强的 T 细胞扩增依赖于 T 细胞内在的 STAT3 信号传导。最后，MDA-7/IL24 修饰的 T 细胞治疗显著抑制了 Hi-Myc 转基因小鼠中自发性前列腺癌的进展。总之，用具有细胞毒性和免疫增强作用的 MDA-7/IL24 武装 T 细胞赋予了消除抗原阴性癌细胞克隆和改善肿瘤内 T 细胞扩增的新能力。这种有前途的方法可用于优化细胞免疫疗法治疗异质性实体瘤，并为抑制肿瘤逃逸提供了一种机制。意义：这项研究描述了一种新策略，通过工程化 T 淋巴细胞产生广谱细胞毒性剂来克服实体瘤的抗原异质性并防止肿瘤逃逸。
