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图1.诱导抗肿瘤免疫的4个关键点
Figure 1 | Four nodes to target when inducing anti-tumour immunity. Multiple arms of immunity can be modulated to enhance the antitumour function of the immune system.a | Elimination of immune suppression by attenuating suppressor cells and their immune suppressive mediators, and through inhibitory receptor blockade. b | Promoting immunogenic cancer-cell death using targeted therapies. c | Enhancing antigen presenting cell （APC） function using immune adjuvants.d | Promoting effector T?cell and macrophage function using agonists. B7?H-, receptor from the B7 family; BTLA, B? and T?lymphocyte attenuator/CD272;α？C-GalCer, α？C-galactosylceramide; CCL?2, chemokine ligand 2;CSF?1, colony stimulating factor 1; CTL, cytotoxic T-lymphocyte; CTLA?4, cytotoxic T?lymphocyte antigen 4/CD152; DNAM?1, DNAX accessory molecule?1/CD226; FcγR, fragment crystallizable gamma receptor;α？GalCer, α？galactosylceramide; GITR, glucocorticoid-induced TNFR family related protein; GM?CSF, granulocyte macrophage colony-stimulating factor; HDAC, histone deacetylase; HIF?1α， on hypoxia-inducible factor?1α； HVEM, herpes virus entry mediator; ICOS, inducible T?cell co-stimulator/CD278; IDO, indoleamine 2,3?dioxygenase; KIR, killer cell immunoglobulin-like receptors; LAG?3, lymphocyte activation gene?3/CD223; M2, M2 macrophage; MDSC, myeloid-derived suppressor cell; NKG2A, inhibitory NK cell receptor CD94; OX40, CD134; PD?1, programmed cell death 1/CD279; PD?1H, PD?1 homologue; PGE2, prostaglandin E2; SIRPα， signal-regulatory protein α； STAT3, signal transducer and activator of transcription 3; STING, stimulator of interferon genes; TIGIT, T?cell immunoreceptor with immunoglobulin and ITIM domains; TH1, type I helper T?cell; Tie2, tunica interna endothelial cell kinase 2; TIM?3, T?cell immunoglobulin and mucin domain 3; TLR, toll-like receptor; TRAIL?R, TNF-related apoptosis-inducing ligand receptor; TREG, regulatory T?cell; VISTA, V?domain immunoglobulin suppressor of T?cell activation.
当诱导抗肿瘤免疫时，有四个可以作为靶点的关键点（图1）。文章提出了很多检验以这四个关键点为靶点的新联合治疗方法的机会（表2），以在不同癌症免疫环境下进行治疗。抗PD-1和抗PD-L1抗体将在未来很多种癌症治疗中将担当基石，目前就已经可以将这些抗体与手术、免疫原性化疗、靶向治疗和放疗联合应用于1型肿瘤中。另外CAR-T细胞ACT策略是一种凭借自身力量发挥作用的联合治疗方法，这种方法结合了与关节点2和关节点4有关的治疗方法。文章预测，通过在更早的时间给予患者联合治疗，50%或以上的癌症（比如黑色素瘤和RCC）可以获得有效控制。
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表1.目前用于临床或正经试验检验的单独靶向免疫治疗药物
*PD?1 specificity not yet validated. AML, acute myeloid leukaemia; B7?H-, receptor from the B7 family; CCL?2, chemokine ligand 2; CD, cluster of differentiation;CLC, chronic lymphocytic leukaemia; CSF?1, colony stimulating factor 1; CTLA?4, cytotoxic T?lymphocyte-associated protein 4/CD152; GITR, glucocorticoidinduced TNFR family-related protein; GM?CSF, granulocyte macrophage colony-stimulating factor; IDO, indoleamine 2,3?dioxygenase; IL?, interleukin; KIR, killer cell immunoglobulin-like receptors; LAG?3, lymphocyte activation gene?3/CD223; MM, multiple myeloma; NKG2A, inhibitory NK cell receptor CD94; OX40, CD134; p53, tumour protein 53; PD?1, programmed cell-death protein 1/CD279; PD?L1, PD ligand 1; Tie2, tunica internal endothelial cell kinase 2; TLR, toll-like receptor; VEGF, vascular endothelial growth factor.
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表2.可用的治疗癌症患者的免疫治疗方法
与大量的不良事件有关的抗CTL1-4抗体和其他激活剂是否在这些患者中成为了固定的治疗方法依赖于针对肿瘤微环境作用机制的新治疗策略和毒性控制。补充PD-1/PD-L1相互作用的新型检查点抑制通路很有希望提高有适应性耐药表现的肿瘤的敏感性。肿瘤细胞或免疫细胞中的PD-L1（和其它他配体）表达、TIL浸润，以及肿瘤细胞的某些基因标记将有助于根据患者的“免疫组”对患者进行分层，为每种类型肿瘤提供最好的联合治疗方案的信息。单一的干预措施，特别是耗尽TREG细胞（靶向关节点1）可能与抗PD-L1为基础的联合治疗一样有效，虽然肿瘤内部的TREG细胞中的合适靶标仍需要确认。类似的，某些表现出适应性耐药（Ⅰ型TME）或免疫耐受（Ⅳ型TME）的肿瘤可能包含大量M2极化巨噬细胞，为了控制或减少肿瘤生长，可以将这种细胞转变为M1表型。可以肯定的是，Ⅳ型TM3肿瘤包含TIL，但是却不表现出明显的适应性耐药，这种肿瘤可以采用以其它非PD-1/PD-L1受体为靶点的治疗方式，也可以采用非效应T细胞策略。这些治疗方案仍然处于研发早期，但是很可能在不久的将来走进临床。$ m2 X2 T- t( [/ w| 欢迎光临 干细胞之家 - 中国干细胞行业门户第一站 (http://www.stemcell8.cn/) | Powered by Discuz! X1.5 |