Trono Paola, Sistigu Antonella, Palermo Belinda, Ciliberto Gennaro, Nisticò Paola
Unit of Tumor Immunology and Immunotherapy, Department of Research, Advanced Diagnostics and Technological Innovation Regina Elena National Cancer Institute, via Elio Chianesi 53, Rome 00144, Italy.
Department of General Pathology and Physiopathology, Università Cattolica del Sacro Cuore, largo Francesco Vito 1, Rome 00168, Italy.
Emerg Top Life Sci. 2017 Dec 12;1(5):471-486. doi: 10.1042/ETLS20170068.
Targeting of immune checkpoint blockers (ICBs), such as cytotoxic T-lymphocyte antigen-4 and programmed-death 1/programmed-death ligand 1, has dramatically changed the landscape of cancer treatment. Seeing patients who were refractory to conventional therapy recover after immunotherapy, with high rates of objective durable responses and increased overall survival, has raised great enthusiasm in cancer care and research. However, to date, only a restricted portion of patients benefit from these therapies, due to natural and acquired resistance relying on the ever-evolving cross-talk between tumor and stromal cells. Here, we review the convergence of tumor-intrinsic and -extrinsic cues, both affecting tumor plasticity and tumor stroma leading to an immunosuppressive tumor microenvironment, which may account for the heterogeneous responses and resistance to ICB therapies. A deeper knowledge of the mechanisms and fingerprints involved in natural and acquired resistance is likely to bring clinical benefit to the majority of patients, offering important clues for overcoming drug resistance and boosting the effectiveness of treatment. We discuss the need to define tumor subtypes based on the tumor, immune and stromal gene signature and propose that the better we understand tumor mesenchymal traits, the more we will be able to identify predictive biomarkers of response to ICB treatments.
靶向免疫检查点阻断剂（ICB），如细胞毒性T淋巴细胞抗原4和程序性死亡蛋白1/程序性死亡配体1，已极大地改变了癌症治疗的格局。看到那些对传统疗法难治的患者在免疫治疗后康复，出现高比例的客观持久反应并提高了总生存率，这在癌症护理和研究领域引发了极大的热情。然而，迄今为止，由于天然和获得性耐药依赖于肿瘤细胞与基质细胞之间不断演变的相互作用，只有一小部分患者能从这些疗法中获益。在此，我们综述了肿瘤内在和外在信号的汇聚，二者均影响肿瘤可塑性和肿瘤基质，导致免疫抑制性肿瘤微环境，这可能是ICB治疗产生异质性反应和耐药性的原因。深入了解天然和获得性耐药所涉及的机制和特征可能会给大多数患者带来临床益处，为克服耐药性和提高治疗效果提供重要线索。我们讨论了基于肿瘤、免疫和基质基因特征定义肿瘤亚型的必要性，并提出我们对肿瘤间充质特征了解得越透彻，就越能够识别出对ICB治疗反应的预测性生物标志物。
