Wang Qiaohong, Wu Xia
Department of Obstetrics & Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, PR China.
Department of Obstetrics & Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, PR China.
Int Immunopharmacol. 2017 May;46:210-219. doi: 10.1016/j.intimp.2017.03.015. Epub 2017 Mar 18.
PD-1/PD-L1 blockade appears to be a very promising immunotherapy with significant clinical benefits and durable responses in multiple tumor types. However, the effectual clinical benefits of PD-1/PD-L1 blockade are hampered by a high rate of primary resistance, where patients do not respond to PD-1/PD-L1 blockade initially. And more distressingly, most patients eventually develop acquired resistance after an initial response to PD-1/PD-L1 blockade. The mechanisms underlying primary and acquired resistance to PD-1/PD-L1 blockade have remained ambiguous. This review documents in detail the current understanding of the mechanisms through which resistance to anti-PD1/PD-L1 therapy occurs. The mechanisms underlying primary resistance to PD-1/PD-L1 blockade contain several immunoregulatory factors affecting tumor-specific immune responses within the immune microenvironment, co-enrichment of a group of 26 transcriptomic signatures (named innate anti-PD-1 resistance (IPRES) signatures) and cancer-cell-autonomous cues. The mechanism attributable to acquired resistance harbors evolution of neoantigen landscape, mutations of JAK and β-2-microglobulin, and epigenetic stability of exhausted T cells. At last, the promising therapeutic strategies to sensitize the resistant patients are also briefly discussed.
PD-1/PD-L1阻断似乎是一种非常有前景的免疫疗法，在多种肿瘤类型中具有显著的临床益处和持久反应。然而，PD-1/PD-L1阻断的有效临床益处受到高比例原发性耐药的阻碍，即患者最初对PD-1/PD-L1阻断无反应。更令人苦恼的是，大多数患者在对PD-1/PD-L1阻断产生初始反应后最终会产生获得性耐药。对PD-1/PD-L1阻断原发性和获得性耐药的潜在机制仍不明确。本综述详细记录了目前对抗PD-1/PD-L1治疗耐药发生机制的理解。对PD-1/PD-L1阻断原发性耐药的潜在机制包括影响免疫微环境中肿瘤特异性免疫反应的几种免疫调节因子、一组26种转录组特征（称为先天性抗PD-1耐药（IPRES）特征）的共同富集以及癌细胞自主线索。获得性耐药的机制包括新抗原格局的演变、JAK和β-2微球蛋白的突变以及耗竭T细胞的表观遗传稳定性。最后，还简要讨论了使耐药患者敏感的有前景的治疗策略。
