PD-1/PD-L1抑制剂在晚期结直肠癌联合治疗中的研究进展

Recent advances in combination therapy of PD-1/PD-L1 inhibitors for advanced colorectal cancer

结直肠癌(colorectal cancer,CRC)是全球最常见的消化系统恶性肿瘤,因早期诊断率低,多数患者初诊时已处于进展期,预后极差。单用免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)仅有部分高度微卫星不稳定(microsatellite instability-high,MSI-H)的晚期CRC患者能获益,大部分患者对免疫治疗存在抵抗,抵抗机制可能与肿瘤微环境(tumor microenvironment,TME)中的CD8^+T淋巴细胞缺乏相关。联合治疗可通过诱导CD8^+T淋巴细胞富集与活化,上调PD-1/PD-L1的表达,降低Treg细胞比例等方式消除肿瘤的免疫逃逸。为了进一步拓宽免疫治疗的获益人群,找到能获益的早期CRC患者,评价免疫治疗疗效及预后,需要研究新的预测标志物,如肿瘤突变负荷(tumor mutational burden,TMB)、免疫评分等。本文就ICIs与化疗、放疗、靶向治疗以及溶瘤病毒的联合作用机制及在晚期CRC中的最新进展进行综述。

Colorectal cancer(CRC)is the most common malignant tumor of the digestive system worldwide.Because of the low early diagnosis rate of CRC,most patients are initially diagnosed in an advanced stage and have poor prognosis.Immune checkpoint inhibitors(ICIs)alone can only benefit some patients with MSI-H advanced CRC.Most patients are resistant to immunotherapy,and the mechanism of resistance may be associated with the lack of CD8+T lymphocytes in the tumor microenvironment.Combined immunotherapy can eliminate the immune escape mechanism of tumors by inducing the enrichment and activation of CD8+T lymphocytes,upregulating PD-1/PD-L 1 activation,and reducing Treg cell proportions.To enable more patients to benefit from immunotherapy,including those with early CRC,and to evaluate the efficacy and prognosis of immunotherapy,new predictive markers,such as the tumor mutation burden,and immunoscore need to be assessed.This article reviews the interaction mechanism and recent progress of ICIs with oncolytic viruses in chemotherapy,radiotherapy,and targeted therapy for advanced CRC.