Department of Pathology & Laboratory Medicine, University of British Columbia Hospital, Koerner Pavilion, #G-227 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada.
Department of Pathology & Laboratory Medicine, University of British Columbia Hospital, Koerner Pavilion, #G-227 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada.
Semin Cancer Biol. 2018 Oct;52(Pt 2):39-52. doi: 10.1016/j.semcancer.2017.10.001. Epub 2017 Oct 5.
The first generation of immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-1/PD-L1) targeted natural immune homeostasis pathways, co-opted by cancers, to drive anti-tumor immune responses. These agents led to unprecedented results in patients with previously incurable metastatic disease and may become first-line therapies for some advanced cancers. However, these agents are efficacious in only a minority of patients. Newer strategies are becoming available that target additional immunomodulatory mechanisms to activate patients' own anti-tumor immune responses. Herein, we present a succinct summary of emerging immune targets with reported pre-clinical efficacy that have progressed to active investigation in clinical trials. These emerging targets include co-inhibitory and co-stimulatory markers of the innate and adaptive immune system. In this review, we discuss: 1) T lymphocyte markers: Lymphocyte Activation Gene 3 [LAG-3], T-cell Immunoglobulin- and Mucin-domain-containing molecule 3 [TIM-3], V-domain containing Ig Suppressor of T cell Activation [VISTA], T cell ImmunoGlobulin and ITIM domain [TIGIT], B7-H3, Inducible T-cell Co-stimulator [ICOS/ICOS-L], CD27/CD70, and Glucocorticoid-Induced TNF Receptor [GITR]; 2) macrophage markers: CD47/Signal-Regulatory Protein alpha [SIRPα] and Indoleamine-2,3-Dioxygenase [IDO]; and 3) natural killer cell markers: CD94/NKG2A and the Killer Immunoglobulin-like receptor [KIR] family. Finally, we briefly highlight combination strategies and potential biomarkers of response and resistance to these cancer immunotherapies.
第一代免疫检查点抑制剂（抗 CTLA-4 和抗 PD-1/PD-L1）针对癌症所利用的天然免疫稳态途径，以驱动抗肿瘤免疫反应。这些药物在以前无法治愈的转移性疾病患者中取得了前所未有的效果，并且可能成为某些晚期癌症的一线治疗方法。然而，这些药物仅在少数患者中有效。新的策略正在出现，这些策略针对额外的免疫调节机制，以激活患者自身的抗肿瘤免疫反应。在此，我们简要总结了具有报道的临床前疗效的新兴免疫靶标，这些靶标已在临床试验中进行了积极的研究。这些新兴的靶标包括先天和适应性免疫系统的共抑制和共刺激标志物。在这篇综述中，我们讨论了：1）T 淋巴细胞标志物：淋巴细胞激活基因 3 [LAG-3]、T 细胞免疫球蛋白和粘蛋白结构域包含分子 3 [TIM-3]、含 V 结构域的 IgT 细胞激活抑制物 [VISTA]、T 细胞免疫球蛋白和 ITIM 结构域 [TIGIT]、B7-H3、诱导性 T 细胞共刺激物 [ICOS/ICOS-L]、CD27/CD70 和糖皮质激素诱导的肿瘤坏死因子受体 [GITR]；2）巨噬细胞标志物：CD47/信号调节蛋白α [SIRPα]和吲哚胺 2,3-双加氧酶 [IDO]；3）自然杀伤细胞标志物：CD94/NKG2A 和杀伤免疫球蛋白样受体 [KIR]家族。最后，我们简要强调了这些癌症免疫疗法的联合策略和潜在的反应和耐药生物标志物。
