Department of Anesthesiology, Wexner Medical Center, College of Medicine, The Ohio State University, Columbus, OH 43210.
The Ohio State University, Comprehensive Cancer Center, Department of Cancer Biology and Genetics, Wexner Medical Center, Columbus, OH 43210.
Proc Natl Acad Sci U S A. 2024 Jul 16;121(29):e2408649121. doi: 10.1073/pnas.2408649121. Epub 2024 Jul 9.
Elevated levels of in solid and liquid malignancies correlate with aggressiveness of the disease. In this manuscript, we show that targets transcripts encoding IcosL, the ligand for Inducible T-cell costimulator (Icos), thus impairing the ability of T cells to recognize and eliminate malignant cells. We specifically found that overexpression of in B cells of Eµ- mice causes loss of IcosL expression as they progress toward malignancy. Similarly, in mice where expression is controlled by a Cre-Tet-OFF system, induction led to malignant infiltrates lacking expression. Conversely, turning OFF led to tumor regression and emergence of infiltrates composed of IcosL-positive B cells and Icos-positive T cells forming immunological synapses. Therefore, we next engineered malignant cells to express IcosL, in order to determine whether expression would increase tumor infiltration by cytotoxic T cells and reduce tumor progression. Indeed, overexpressing an -encoding cDNA in MC38 murine colon cancer cells before injection into syngeneic C57BL6 mice reduced tumor size and increased intratumor CD8+ T cell infiltration, that formed synapses with IcosL-expressing MC38 cells. Our results underscore the fact that by targeting transcripts, impairs the infiltration of tumors by cytotoxic T cells, as well as the importance of IcosL on enhancing the immune response against malignant cells. These findings should lead to the development of more effective anticancer treatments based on maintaining, increasing, or restoring IcosL expression by malignant cells, along with impairing activity.
在实体和液体恶性肿瘤中升高的水平与疾病的侵袭性相关。在本文中，我们表明 靶向编码吲哚胺 2,3-双加氧酶（IDO）的配体诱导型 T 细胞共刺激因子（ICOS）的转录本，从而损害 T 细胞识别和消除恶性细胞的能力。我们特别发现，Eμ-小鼠的 B 细胞中 过表达导致 IcosL 表达丧失，因为它们向恶性转化进展。同样，在由 Cre-Tet-OFF 系统控制 的小鼠中， 诱导导致缺乏 表达的恶性浸润。相反，关闭 导致肿瘤消退并出现由表达 IcosL 的 B 细胞和形成免疫突触的 Icos 阳性 T 细胞组成的浸润。因此，我们接下来设计了表达 IcosL 的恶性细胞，以确定 表达是否会增加细胞毒性 T 细胞对肿瘤的浸润并减少肿瘤进展。事实上，在将编码 cDNA 的 MC38 小鼠结肠癌细胞注射到同种系 C57BL6 小鼠之前过表达 ，可减少肿瘤大小并增加肿瘤内 CD8+T 细胞浸润，该浸润与表达 IcosL 的 MC38 细胞形成突触。我们的结果强调了这样一个事实，即通过靶向 转录本， 损害了细胞毒性 T 细胞对肿瘤的浸润，以及 IcosL 增强针对恶性细胞的免疫反应的重要性。这些发现应该会导致开发更有效的抗癌治疗方法，这些方法基于维持、增加或恢复恶性细胞表达 IcosL，同时损害 活性。
