【摘要】 抗程序性死亡受体/配体1 (PD-1/PD-L1)单抗因其在多种恶性肿瘤中临床疗效良好且患者能获得长期缓解,被认为是有潜力的抗肿瘤药物,但其高发的耐药问题(包括原发性及获得性耐药)仍不容忽视。目前研究显示抗PD-1/PD-L1单抗的原发性耐药与肿瘤免疫微环境动态变化、肿瘤突变负荷及致癌通路激活等因素相关。获得性耐药机制包括新抗原谱系演化,JAK1/JAK2、β2-微球蛋白基因突变及衰竭T细胞表观遗传学稳定性。因此,可通过联合放化疗增强肿瘤免疫原性,通过阻断共表达的抑制性受体、细胞因子等打破肿瘤微环境免疫抑制状态,提高抗PD-1/PD-L1单抗的临床疗效。更多还原

【Abstract】 Anti-programmed death receptor/ligand 1(PD-1/PD-L1) monoclonal antibody is recognized as a very promising anti-tumor drug because of dramatic clinical response and durable remission in a variety of malignant tumor. Nonetheless, the high rate of drug resistance should not be ignored, including primary and acquired resistance. Current studies have shown that primary resistance contain dynamic variation of tumor immune microenvironment, tumor mutation burden and activation of oncogenic signaling pathways. The acquired resistance mechanism include the evolution of neoantigen landscape, mutation of JAK1/JAK2, β2-microglobulin gene mutations, and epigenetic stability of exhausted T cells. Therefore, in order to improve the clinical efficacy of anti-PD-1/PD-L1 monoclonal antibodies, the following strategies can be adopted, combination of chemoradiotherapy to enhance tumor immunogenicity, and blocking co-inhibitory receptors and cytokines to break the tumor microenvironment immunosuppressive status.更多还原