结直肠癌是与癌症相关的死亡的第三大原因，也是癌症的第三大常见原因。由于晚期转移性结直肠癌（mCRC）的五年生存率为14％，需要新的治疗策略。免疫检查点阻断利用个体的免疫系统来对抗癌症，在临床上具有影响力；然而，对于结直肠癌来说，这种方法只对处理错配修复（MMR）缺陷的癌症有效并获得批准。此外，MMR缺陷的mCRC的长期结果表明，大多数患者未能痊愈并最终产生治疗抵抗性。我们假设通过靶向TGF-β信号转导，可以增强MMR缺陷的结直肠癌细胞受到免疫介导的T细胞杀伤。通过使用GLPG-0187，一种抑制多个整合素受体和TGF-β的抑制剂，我们证明在MMR缺陷的HCT116或p53null HCT116人类结直肠癌细胞中，GLPG-0187对细胞毒性影响最小。GLPG-0187促进了TALL-104 T淋巴细胞对结直肠癌细胞的显著免疫杀伤，并减少了HCT116 p53-null细胞中的磷酸SMAD2含量，无论是否有外源性TGF-β存在。我们观察到，在以T细胞激活剂量（4µM）处理的TALL-104细胞中，CCL20、CXCL5、催乳素和TRAIL-R3减少，而GDF-15增加。我们的结果表明，通过一种整合素受体抑制剂抑制TGF-β信号传导，可以增强T细胞对MMR缺陷的结直肠癌细胞的杀伤，并且建议进一步研究抗GDF-15联合TGF-β阻断的治疗MMR缺陷mCRC。我们的结果支持通过整合素受体阻断来靶向TGF-β信号传导途径的免疫基于治疗策略的开发用于结直肠癌的治疗。AJCR版权所有©2023。

Colorectal cancer is the third leading cause of cancer-related death and the third most common cause of cancer. As the five-year survival with advanced metastatic colorectal cancer (mCRC) is 14%, new treatment strategies are needed. Immune checkpoint blockade, which takes advantage of an individual's immune system to fight cancer, has an impact in the clinic; however, for CRC, it is only effective and approved for treating mismatch repair (MMR)-deficient cancer. Moreover, long-term outcomes in MMR-deficient mCRC suggest that most patients are not cured and eventually develop therapy resistance. We hypothesized that targeting TGF-β signaling may enhance immune-mediated T-cell killing by MMR-deficient CRC cells. Using GLPG-0187, an inhibitor of multiple integrin receptors and TGF-β, we demonstrate minimal cytotoxicity against MMR-deficient HCT116 or p53null HCT116 human CRC cells. GLPG-0187 promoted significant immune cell killing of the CRC cells by TALL-104 T lymphoblast cells and reduced phosphoSMAD2 in HCT116 p53-null cells either in the absence or presence of exogenous TGF-β. We observed a reduction in CCL20, CXCL5, prolactin, and TRAIL-R3, while GDF-15 was increased in TALL-104 cells treated with a T-cell activating dose of GLPG-0187 (4 µM). Our results suggest that TGF-β signaling inhibition by a general integrin receptor inhibitor may boost T-cell killing of MMR-deficient colorectal cancer cells and suggest that a combination of anti-GDF-15 in combination with TGF-β blockade be further investigated in the treatment of MMR-deficient mCRC. Our results support the development of a novel immune-based therapeutic strategy to treat colorectal cancer by targeting the TGF-β signaling pathway through integrin receptor blockade.AJCR Copyright © 2023.