Yan Lin-Hai, Liu Xiao-Liang, Mo Si-Si, Zhang Di, Mo Xian-Wei, Tang Wei-Zhong
Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital Nanning 530021, Guangxi Zhuang Autonomous Region, China.
Guangxi Clinical Research Center for Colorectal Cancer Nanning 530021, Guangxi Zhuang Autonomous Region, China.
Am J Transl Res. 2021 Mar 15;13(3):923-934. eCollection 2021.
First-generation immunological checkpoint inhibitors, such as CTLA-4, PD-L1 and PD-1 exhibit significant advantages over conventional cytotoxic drugs, such as oxaliplatin and 5-FU, for the treatment of colorectal cancer. However, these inhibitors are not ideal due to their low objective response rate and the vulnerability of these treatment methods when faced with emerging drug resistant cancers. This study summarizes the immunological characteristics of colorectal cancer treatment, and analyzes the ways in which OX40 may improve the efficacy of these treatments. Activation of the OX40 signaling pathway can enhance the activity of CD4+/CD8+ T cells and inhibit the function of Treg. Simultaneously, OX40 can directly inhibit the expression of Foxp3, affect the inhibitory function of Treg, and inhibit the immunosuppressive factors in the tumor microenvironment so as to reverse immune escape and reverse drug resistance. Therefore, OX40 is an important target for treating colorectal cancer in "cold tumors" with less immunogenicity.
第一代免疫检查点抑制剂，如细胞毒性T淋巴细胞相关抗原4（CTLA-4）、程序性死亡配体1（PD-L1）和程序性死亡受体1（PD-1），在治疗结直肠癌方面比传统细胞毒性药物，如奥沙利铂和5-氟尿嘧啶（5-FU）具有显著优势。然而，由于这些抑制剂的客观缓解率较低，且面对新出现的耐药性癌症时这些治疗方法较为脆弱，因此并不理想。本研究总结了结直肠癌治疗的免疫学特征，并分析了OX40可能提高这些治疗疗效的方式。OX40信号通路的激活可增强CD4+/CD8+T细胞的活性并抑制调节性T细胞（Treg）的功能。同时，OX40可直接抑制叉头框蛋白3（Foxp3）的表达，影响Treg的抑制功能，并抑制肿瘤微环境中的免疫抑制因子，从而逆转免疫逃逸和耐药性。因此，OX40是治疗免疫原性较低的“冷肿瘤”型结直肠癌的重要靶点。
