State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China.
The First People's Hospital of Lianyungang, Lianyungang, PR China.
Int Immunopharmacol. 2022 Nov;112:109233. doi: 10.1016/j.intimp.2022.109233. Epub 2022 Sep 18.
Colorectal cancer (CRC) is the third most common cancer in the world. Recently, many clinical studies have demonstrated the therapeutic potential of immune checkpoint therapy combined with inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2) in colon cancer. Compound B37, identified in our previous experiment, is an apo-form indoleamine-2,3-dioxygenase 1 inhibitor (apo-IDO1 inhibitor), which has been shown to significantly suppress tumor growth combined with an anti-PD1 antibody. We speculated whether this apo-IDO inhibitor (B37) combined with a VEGFR2 inhibitor (apatinib) would further improve its anti-tumor activity. Therefore, a syngeneic mouse colon cancer model (mouse colon cancer cell line CT26) was established to investigate the anti-tumor activity of B37 combined with apatinib. As expected, the combination of B37 and apatinib (VEGFR2 inhibitor) improved the therapeutic effect compared with apo-IDO1 inhibitor and apatinib monotherapy, as shown by the reduced growth of transplanted tumors, weakened proliferation, and increased apoptosis of cancer cells. Specifically, there was a 24.8% reduction in tumor volume using apatinib and 31.3% reduction using B37. The combination-treated group showed remarkable inhibition of tumor growth (52.2%). For tumor weight, there was a 29.2% reduction in the apatinib-treated group and 35.0% reduction in the B37-treated group. The combination-treated group showed a 56.3% reduction. Moreover, the combination therapy reprogrammed the immune microenvironment by increasing infiltration of CD4 and CD8 T cells, decreasing the ratio of regulatory T cells, and promoting the killing ability of T cells manifested by elevated expression of IFN-γ and granzyme B in the combination-treated group. Our study indicates that the combination of apo-IDO1 inhibitor and apatinib is a promising strategy for CRC therapy.
结直肠癌（CRC）是世界上第三大常见癌症。最近，许多临床研究表明，免疫检查点疗法联合血管内皮生长因子受体 2（VEGFR2）抑制剂在结肠癌治疗中具有潜在的治疗效果。在我们之前的实验中发现的化合物 B37 是一种apo 形式的吲哚胺 2,3-双加氧酶 1 抑制剂（apo-IDO1 抑制剂），已证明与抗 PD1 抗体联合使用可显著抑制肿瘤生长。我们推测这种 apo-IDO 抑制剂（B37）与 VEGFR2 抑制剂（阿帕替尼）联合使用是否会进一步提高其抗肿瘤活性。因此，建立了同源小鼠结肠癌模型（小鼠结肠癌细胞系 CT26），以研究 B37 联合阿帕替尼的抗肿瘤活性。正如预期的那样，与 apo-IDO1 抑制剂和阿帕替尼单药治疗相比，B37 与阿帕替尼（VEGFR2 抑制剂）的联合使用改善了治疗效果，表现为移植瘤的生长减少、癌细胞增殖减弱和凋亡增加。具体而言，阿帕替尼治疗组肿瘤体积减少 24.8%，B37 治疗组肿瘤体积减少 31.3%。联合治疗组显示出显著的肿瘤生长抑制（52.2%）。对于肿瘤重量，阿帕替尼治疗组减少 29.2%，B37 治疗组减少 35.0%。联合治疗组减少 56.3%。此外，联合治疗通过增加 CD4 和 CD8 T 细胞的浸润、降低调节性 T 细胞的比例以及通过联合治疗组中 IFN-γ 和颗粒酶 B 表达的升高来促进 T 细胞的杀伤能力，从而重新编程免疫微环境。我们的研究表明，apo-IDO1 抑制剂和阿帕替尼的联合治疗是 CRC 治疗的一种有前途的策略。
