免疫球蛋白样转录子4:癌症免疫治疗新靶点

Immunoglobulin-like transcript 4:a novel immunotherapeutic target for cancer

目的总结免疫球蛋白样转录子(ILT)4在肿瘤微环境中的表达、功能及其最新临床转化研究进展,分析阻断ILT4在克服免疫检查点抑制剂(ICIs)耐药中的临床价值。方法在PubMed及ClinicalTrial.gov中以“ILT4、LILRB2、cancer”为英文关键词,检索1998-01-01-2023-03-31发表的所有相关文献。纳入标准:ILT4在肿瘤中表达的研究;ILT4与肿瘤发生发展关系及潜在分子机制的相关研究;ILT4参与肿瘤免疫治疗的转化研究;ILT4单克隆抗体在实体肿瘤中的临床研究。排除标准:与恶性肿瘤无关的文献;数据不完整的文献;低质量和陈旧类文献。最终共纳入文献57篇。结果ILT4是主要表达于髓系细胞的新型免疫检查点分子。ILT4在恶性肿瘤的肿瘤细胞及微环境髓系细胞如单核细胞、肿瘤相关巨噬细胞、树突状细胞和髓源性抑制细胞中高表达,促进了肿瘤的恶性生物学行为,并构建了免疫抑制性肿瘤微环境,直接或间接促进肿瘤进展。在临床前研究中,阻断ILT4能够抑制肿瘤的恶性增殖转移及免疫逃逸,增强免疫治疗的疗效,最终发挥抗肿瘤效应。目前已有多种针对性的ILT4单克隆抗体研发出来并进入早期临床试验阶段,初步证实阻断ILT4具有一定的抗肿瘤活性,并可增强PD-1/PD-L1抑制剂的疗效。结论ILT4是恶性肿瘤免疫治疗新靶点,阻断ILT4为抑制肿瘤进展和克服免疫治疗耐药提供了很有潜力的策略,但是后续临床应用面临的诸多挑战值得进一步探索。

Objective To review the expression and function of immunoglobulin-like transcript(ILT)4 in the tumor microenvironment(TME)and its latest clinical transformation researches,highlighting the importance of ILT4 blockade in overcoming immunoresistance to immune checkpoint inhibitors(ICIs).Methods We searched all the literature on ILT4 and cancer and the clinical trilas between 1998.01.01 and 2023.03.31 from Pubmed and ClinicalTrial.gov with the keywords of"ILT4,LILRB2 and cancer",Inclusion criteria:ILT4 expression in cancer;the correlation of ILT4 with tumor progression and underlying mechanisms;the transformation research of ILT4 in tumor immunotherapy;the clinical trials of ILT4 monoclonal antibodies in solid cancer.Exclusion criteria:literature not related with tumor;literature with incomplete data;low-quality or obsolete literature.Results ILT4 is a novel checkpoint molecule which is mainly expressed in myeloid cells.ILT4 is enriched in both tumor cells and myeloid cells of TME,including monocytes,tumor-associated macrophages,dendritic cells and myeloid-derived suppressive cells.ILT4 promotes tumor progression directly via induction of the malignant tumor behaviors,and indirectly via reprogramming immunosuppressive TME.In the pre-clinical studies,ILT4 blockade inhibited malignant tumor behaviors,reversed the suppressive TME,improved the efficacy of ICIs,and finally restricted tumor progression.So far,several specific ILT4 monoclonal antibodies have been developed for cancer treatment,and some of them are undergoing phase I/II clinical trials.The preliminary results have demonstrated their anti-tumor activity,especially their role in enhancing ICI efficacy.Conclusion ILT4 is a novel checkpoint target for tumor immunotherapy.ILT4 blockade is a promising strategy to combat cancer and overcome immune checkpoint inhibitor resistance.However,the clinical application of ILT4 antibodies still faces many challenges worthy further exploring.