Medical Oncology Department, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Costa del Sol, 29603 Marbella, Malaga, Spain.
Immunology and Immunotherapy Department, Clinica Universidad de Navarra (CUN), Center for Applied Medical Research (CIMA), Universidad de Navarra (UNAV), 31008 Pamplona, Spain.
Drug Resist Updat. 2020 Dec;53:100718. doi: 10.1016/j.drup.2020.100718. Epub 2020 Jul 15.
Cancer is one of the main public health problems in the world. Systemic therapies such as chemotherapy and more recently target therapies as well as immunotherapy have improved the prognosis of this large group of complex malignant diseases. However, the frequent emergence of multidrug resistance (MDR) mechanisms is one of the major impediments towards curative treatment of cancer. While several mechanisms of drug chemoresistance are well defined, resistance to immunotherapy is still insufficiently unclear due to the complexity of the immune response and its dependence on the host. Expression and regulation of immune checkpoint molecules (such as PD-1, CD279; PD-L1, CD274; and CTLA-4, CD152) play a key role in the response to immunotherapy. In this regard, immunotherapy based on immune checkpoints inhibitors (ICIs) is a common clinical approach for treatment of patients with poor prognosis when other first-line therapies have failed. Unfortunately, about 70 % of patients are classified as non-responders, or they progress after initial response to these ICIs. Multiple factors can be related to immunotherapy resistance: characteristics of the tumor microenvironment (TME); presence of tumor infiltrating lymphocytes (TILs), such as CD8 + T cells associated with treatment-response; presence of tumor associated macrophages (TAMs); activation of certain regulators (like PIK3γ or PAX4) found present in non-responders; a low percentage of PD-L1 expressing cells; tumor mutational burden (TMB); gain or loss of antigen-presenting molecules; genetic and epigenetic alterations correlated with resistance. This review provides an update on the current state of immunotherapy resistance presenting targets, biomarkers and remedies to overcome such resistance.
癌症是世界主要公共卫生问题之一。化疗等系统治疗以及最近的靶向治疗和免疫疗法改善了这一大组复杂恶性疾病的预后。然而，多药耐药（MDR）机制的频繁出现是癌症治愈治疗的主要障碍之一。虽然几种药物耐药机制已经得到很好的定义，但由于免疫反应的复杂性及其对宿主的依赖性，免疫疗法耐药的机制仍不清楚。免疫检查点分子（如 PD-1、CD279；PD-L1、CD274；和 CTLA-4、CD152）的表达和调节在免疫治疗反应中起着关键作用。在这方面，基于免疫检查点抑制剂（ICIs）的免疫疗法是治疗预后不良患者的常用临床方法，当其他一线治疗失败时。不幸的是，约 70%的患者被归类为无反应者，或在对这些 ICI 最初反应后进展。多种因素可能与免疫治疗耐药有关：肿瘤微环境（TME）的特征；肿瘤浸润淋巴细胞（TILs）的存在，如与治疗反应相关的 CD8+T 细胞；肿瘤相关巨噬细胞（TAMs）的存在；某些调节剂的激活（如 PIK3γ 或 PAX4）在无反应者中发现；PD-L1 表达细胞的百分比低；肿瘤突变负担（TMB）；抗原呈递分子的获得或丧失；与耐药相关的遗传和表观遗传改变。本综述介绍了免疫治疗耐药的现状，提出了克服耐药的靶点、生物标志物和治疗方法。
