T细胞粘附分子作为癌症免疫治疗的潜在靶点：CD226和CD2-动脉网

Revisiting T-cell adhesion molecules as potential targets for cancer immunotherapy: CD226 and CD2

Nature 等信源发布 2024-10-01 12:51

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AbstractCancer immunotherapy aims to initiate or amplify immune responses that eliminate cancer cells and create immune memory to prevent relapse. Immune checkpoint inhibitors (ICIs), which target coinhibitory receptors on immune effector cells, such as CTLA-4 and PD-(L)1, have made significant strides in cancer treatment.

摘要癌症免疫疗法旨在启动或扩增免疫反应，消除癌细胞并产生免疫记忆以防止复发。免疫检查点抑制剂（ICIs）靶向免疫效应细胞上的共抑制受体，如CTLA-4和PD-（L）1，在癌症治疗方面取得了重大进展。

However, they still face challenges in achieving widespread and durable responses. The effectiveness of anticancer immunity, which is determined by the interplay of coinhibitory and costimulatory signals in tumor-infiltrating immune cells, highlights the potential of costimulatory receptors as key targets for immunotherapy.

然而，它们在实现广泛和持久的反应方面仍然面临挑战。抗癌免疫的有效性由肿瘤浸润性免疫细胞中共抑制和共刺激信号的相互作用决定，突出了共刺激受体作为免疫治疗关键靶点的潜力。

This review explores our current understanding of the functions of CD2 and CD226, placing a special emphasis on their potential as novel agonist targets for cancer immunotherapy. CD2 and CD226, which are present mainly on T and NK cells, serve important functions in cell adhesion and recognition. These molecules are now recognized for their costimulatory benefits, particularly in the context of overcoming T-cell exhaustion and boosting antitumor responses.

这篇综述探讨了我们目前对CD2和CD226功能的理解，特别强调了它们作为癌症免疫治疗的新型激动剂靶标的潜力。主要存在于T细胞和NK细胞上的CD2和CD226在细胞粘附和识别中起重要作用。这些分子现在因其共刺激益处而被认可，特别是在克服T细胞衰竭和增强抗肿瘤反应的背景下。

The importance of CD226, especially in anti-TIGIT therapy, along with the CD2‒CD58 axis in overcoming resistance to ICI or chimeric antigen receptor (CAR) T-cell therapies provides valuable insights into advancing beyond the current barriers of cancer immunotherapy, underscoring their promise as targets for novel agonist therapy..

CD226的重要性，特别是在抗TIGIT治疗中，以及CD2-CD58轴在克服对ICI或嵌合抗原受体（CAR）T细胞疗法的抗性方面的重要性，为超越目前癌症免疫疗法的障碍提供了有价值的见解，强调了它们作为新型激动剂疗法靶标的前景。。

IntroductionImmunotherapy has transformed cancer treatment by significantly improving patient outcomes through treatments such as immune checkpoint inhibitors (ICIs) and adoptive T-cell therapy (ACT)1. While immunotherapy has shown promising results across various cancer types, durable responses are seen only in a minority of patients.

引言免疫疗法通过免疫检查点抑制剂（ICI）和过继性T细胞疗法（ACT）1等治疗显着改善患者预后，从而改变了癌症治疗。虽然免疫疗法在各种癌症类型中显示出有希望的结果，但只有少数患者才能看到持久的反应。

Several efforts, such as triggering costimulatory signals with agonistic antibodies, have continued to overcome its challenges and expand its effectiveness.Costimulation is crucial for full T-cell activation along with cytokine support, as stimulation solely through the T-cell receptor (TCR) complex can induce anergy2.

一些努力，例如用激动性抗体触发共刺激信号，继续克服其挑战并扩大其有效性。共刺激对于完全T细胞活化以及细胞因子支持至关重要，因为仅通过T细胞受体（TCR）复合物的刺激可以诱导无能2。

In particular, it is well known that tumors can impede proper T-cell priming to tumor antigens, a key factor in suppressing the antitumor response. Therapies targeting potent costimulatory signal-delivering receptors, such as 4-1BB, OX40, GITR, ICOS and CD40, have been developed to overcome this challenge.

特别是，众所周知，肿瘤可以阻碍T细胞对肿瘤抗原的正确启动，这是抑制抗肿瘤反应的关键因素。已经开发了针对有效的共刺激信号传递受体（例如4-1BB，OX40，GITR，ICOS和CD40）的疗法来克服这一挑战。

Although agonistic antibodies targeting these receptors have shown promising preclinical effects, their clinical use has been limited by their narrow therapeutic window. This limitation is primarily due to their transient expression upon stimulation, strong constitutive stimulation-induced T-cell dysfunction, and on-target/off-tumor toxicity3,4,5,6.

尽管靶向这些受体的激动性抗体已显示出有希望的临床前作用，但其临床应用受到其狭窄的治疗窗口的限制。这种限制主要是由于它们在刺激后的瞬时表达，强烈的组成型刺激诱导的T细胞功能障碍以及靶向/非肿瘤毒性3,4,5,6。

Ongoing efforts are being made to overcome the existing limitations of T-cell agonist therapy, including the development of antibodies with tumor-specific activity and the induction of oligomerization in tumor necrosis factor (TNF) receptor superfamily (TNFRSF) costimulatory receptors. Combination treatments with other therapeutics, including chemotherapy or radiotherapy, are also being explored.

目前正在努力克服T细胞激动剂治疗的现有局限性，包括开发具有肿瘤特异性活性的抗体和诱导肿瘤坏死因子（TNF）受体超家族（TNFRSF）共刺激受体的寡聚化。还正在探索与其他疗法（包括化疗或放疗）的联合治疗。

However, challenges such as their transient expression and strong signaling-induc.

然而，诸如它们的瞬时表达和强信号传导等挑战诱导了。

Extracellular regulation

细胞外调节

CD226 activation can be inhibited by its counterpart TIGIT, which outcompetes CD226 for binding to PVR or nectin-2 with a higher affinity than CD22658,59. Studies employing time-resolved FRET (TR-FRET) suggest that TIGIT interferes with CD226 homodimerization in an ECD-dependent manner10. A previous structural study reported the cis-homodimerization of TIGIT, facilitating the conjugation of TIGIT-expressing cells to PVR-expressing cells60 (Fig.

CD226激活可以被其对应物TIGIT抑制，TIGIT以比CD22658,59更高的亲和力竞争CD226与PVR或nectin-2的结合。使用时间分辨FRET（TR-FRET）的研究表明，TIGIT以ECD依赖性方式干扰CD226同源二聚化10。先前的结构研究报道了TIGIT的顺式同源二聚化，促进了TIGIT表达细胞与PVR表达细胞的结合60（图）。

2). However, a recent study by Worboys et al. demonstrated that TIGIT clustering at the IS remained intact even with an inert mutation in its homodimerization site (I42D)55. Nevertheless, it remains unclear whether CD226 also undergoes structural homodimerization. More importantly, further investigation is needed to determine whether the homodimerization of TIGIT or CD226 is induced by ligand binding or if it occurs constitutively.

2）。然而，Worboys等人最近的一项研究表明，即使在其同源二聚化位点（I42D）55中存在惰性突变，IS处的TIGIT聚类仍保持完整。然而，尚不清楚CD226是否也经历了结构同源二聚化。更重要的是，需要进一步研究以确定TIGIT或CD226的同源二聚化是由配体结合诱导的还是组成型发生的。

Another mechanism of TIGIT-mediated CD226 inhibition suggested by the same study is that co-expression of TIGIT in Jurkat cells affects CD226 accumulation at the interface between Jurkat and PVR-expressing Raji cells by impeding CD226 binding to PVR10. However, a recent study presented contradictory findings regarding the localization of CD226 and TIGIT in TCR-rich nanoclusters.

同一研究表明，TIGIT介导的CD226抑制的另一种机制是，TIGIT在Jurkat细胞中的共表达通过阻止CD226与PVR10的结合而影响Jurkat和表达PVR的Raji细胞之间界面处的CD226积累。然而，最近的一项研究提出了关于CD226和TIGIT在富含TCR的纳米团簇中定位的矛盾发现。

Two-color direct stochastic optical reconstruction microscopy (dSTORM) analysis of activated primary human T cells with PLBs containing ICAM-1, OKT3 (anti-CD3) and either nectin-1 or PVR revealed that PVR ligation induces co-localization of CD226 and TIGIT in the cSMAC. Moreover, comparable TIGIT clustering was observed between TIGIT + CD226- and TIGIT + CD226 + T cells in the presence of PVR, indicating that CD226 binding to PVR does not interrupt TIGIT clustering at the IS when PVR is abundant (Fig.

用含有ICAM-1，OKT3（抗CD3）和nectin-1或PVR的PLB对活化的原代人T细胞进行双色直接随机光学重建显微镜（dSTORM）分析，发现PVR连接诱导CD226和TIGIT在cSMAC中的共定位。此外，在PVR存在下，在TIGIT+CD226和TIGIT+CD226+T细胞之间观察到可比的TIGIT聚类，表明当PVR丰富时，CD226与PVR的结合不会中断IS处的TIGIT聚类（图）。

2).Fig. 2: Regulation of C.

2）。图2:C的调节。

This discrepancy might result from the over-representation of TIGIT in Jurkat cells due to TIGIT over-expression. Furthermore, unlike PLBs, Raji cells endogenously express other adhesion molecules, which could indirectly influence the interaction of PVR with CD226 or TIGIT. Considering that the varied expression levels of CD226 and TIGIT depend on T-cell status, it is important to account for the different molecular stoichiometries between these molecules to understand how TIGIT directly regulates CD226 extracellularly..

这种差异可能是由于TIGIT过表达导致TIGIT在Jurkat细胞中过度表达所致。。考虑到CD226和TIGIT的不同表达水平取决于T细胞状态，重要的是要考虑这些分子之间不同的分子化学计量，以了解TIGIT如何直接在细胞外调节CD226。。

Intracellular regulation

细胞内调节

TIGIT has an ITIM and an ITT-like motif in its cytoplasmic domain, which exert an inhibitory signal by recruiting SH2-containing inositol phosphate-1 (SHP-1) upon ligation with PVR in NK cells58,61,62. Unlike in NK cells, it is still controversial whether the ITIM and ITT-like motifs of TIGIT are required for conferring inhibitory functions and CD226 inhibition in T cells..

TIGIT在其细胞质结构域中具有ITIM和ITT样基序，其通过在NK细胞中与PVR连接后募集含有SH2的肌醇磷酸-1（SHP-1）来发挥抑制信号58,61,62。。。

One study with an antibody that specifically recognizes phosphorylated CD226 at Y322 (pY322) demonstrated that co-incubation of Jurkat cells expressing TIGIT WT with SEE-loaded Raji cells expressing PVR attenuated CD226 phosphorylation; this effect was not detected in Jurkat cells expressing a TIGIT mutant (Y225A/Y231A).

；在表达TIGIT突变体（Y225A/Y231A）的Jurkat细胞中未检测到这种作用。

Moreover, treatment with an anti-TIGIT mAb restored CD226 phosphorylation9. These findings suggest that the extracellular modulation of CD226 by TIGIT is integrated into the intracellular signaling of CD226, which is affected by TIGIT phosphorylation (Fig. 2)..

此外，用抗TIGIT mAb治疗可恢复CD226磷酸化9。这些发现表明，TIGIT对CD226的细胞外调节被整合到受TIGIT磷酸化影响的CD226的细胞内信号传导中（图2）。。

However, Banta et al. proposed that the ICD of TIGIT is dispensable for inhibiting CD226 phosphorylation; instead, PD-1 recruits SHP-2 to suppress CD22610 (Fig. 2). When Jurkat cells expressing CD226, TIGIT, and/or PD-1 were stimulated with SEE-pulsed Raji cells expressing PVR and PD-L1, the co-expression of TIGIT and PD-1 elicited greater dephosphorylation of CD226 than did TIGIT or PD-1 alone.

然而，Banta等人提出TIGIT的ICD对于抑制CD226磷酸化是不必要的；相反，PD-1募集SHP-2以抑制CD22610（图2）。当用表达PVR和PD-L1的SEE脉冲Raji细胞刺激表达CD226，TIGIT和/或PD-1的Jurkat细胞时，TIGIT和PD-1的共表达比单独的TIGIT或PD-1引起更大的CD226去磷酸化。

In addition, the expression of either an ICD deletion or a Y225F/Y231F mutant of TIGIT did not reverse the reduced phosphorylation of CD226 induced by the expression of TIGIT WT. Another study using a cell-free reconstitution system including ICDs of TCR signaling components, such as TCRζ, CD226, CD28, PD-1, and SHP2, but excluding TIGIT, also suggested the role of PD-1 in CD226 dephosphorylation.

此外，TIGIT的ICD缺失或Y225F/Y231F突变体的表达并不能逆转由TIGIT WT表达诱导的CD226磷酸化的降低。另一项使用无细胞重建系统的研究，包括TCR信号成分的ICD，如TCRζ，CD226，CD28，PD-1和SHP2，但不包括TIGIT，也表明PD-1在CD226去磷酸化中的作用。

Given that PD-1 is known to localize at the cSMAC of the IS45,63, CD226 could also be regulated by PD-1-recruited SHP-2, which inhibits CD28 activation. However, the proposed mechanism that limits the role of the TIGIT ICD contradicts the findings of previous studies demonstrating the intracellular inhibitory function of TIGIT.

鉴于已知PD-1定位于IS45,63的cSMAC，CD226也可以由PD-1募集的SHP-2调节，其抑制CD28活化。然而，所提出的限制TIGIT ICD作用的机制与先前证明TIGIT细胞内抑制功能的研究结果相矛盾。

Moreover, a study by Banta et al. revealed a slight increase in CD226 phosphorylation upon anti-TIGIT mAb treatment alone, which could not be attributed solely to the dissociation of CD226 from PVR without considering intracellular events. Indeed, a recent study employing various TIGIT mutants that affect glycosylation, dimerization, ligand binding, and downstream signaling further elucidated the role of the TIGIT ECD and ICD in regulating T-cell activation55.

此外，Banta等人的一项研究显示，单独使用抗TIGIT mAb治疗后，CD226磷酸化略有增加，这不能仅归因于CD226与PVR的解离，而不考虑细胞内事件。事实上，最近一项使用影响糖基化，二聚化，配体结合和下游信号传导的各种TIGIT突变体的研究进一步阐明了TIGIT ECD和ICD在调节T细胞活化中的作用55。

TIGIT mutants incapable of binding PVR fail to initiate inhibitory signals, indicating the pivotal role of extracellular events in mediating TIGIT phosphorylation-induced inhibition of T-cell responses. Wh.

不能结合PVR的TIGIT突变体不能启动抑制信号，表明细胞外事件在介导TIGIT磷酸化诱导的T细胞反应抑制中的关键作用。白色。

Under physiological cell-to-cell regulation conditions, various events occur simultaneously, unlike direct regulation between molecules. Thus, discrepancies can arise from this complexity. Nevertheless, understanding how TIGIT directly regulates CD226 is crucial for designing effective anti-TIGIT therapy strategies.

在生理细胞间调节条件下，与分子之间的直接调节不同，各种事件同时发生。因此，这种复杂性可能会产生差异。然而，了解TIGIT如何直接调节CD226对于设计有效的抗TIGIT治疗策略至关重要。

In particular, if TIGIT and PD-1 jointly regulate CD226 activity, this is a compelling rationale for a combined blocking strategy targeting both the PD-(L)1 and TIGIT pathways. Conversely, if TIGIT independently regulates CD226, simultaneous blockade with PD-1 may be unnecessary. Therefore, elucidating the interplay between these molecules is essential for the future clinical implementation of anti-TIGIT therapy..

特别是，如果TIGIT和PD-1共同调节CD226活性，这是针对PD-（L）1和TIGIT途径的组合阻断策略的令人信服的理由。相反，如果TIGIT独立调节CD226，则可能不需要同时阻断PD-1。因此，阐明这些分子之间的相互作用对于未来抗TIGIT治疗的临床实施至关重要。。

Further considerations

进一步考虑

Several unanswered questions remain regarding the regulation of CD226. First, there is variable co-expression of CD226, TIGIT, and PD-1 within T cells. Studies have shown an inverse correlation between CD226 and TIGIT or PD-1 in tumor-infiltrating CD8 + T cells (CD8+TILs). Thus, TIGIT and PD-1 are not always co-expressed regardless of CD226 expression in T cells from both healthy donors and patients with cancer9,55,64.

关于CD226的监管仍有几个悬而未决的问题。首先，T细胞内CD226，TIGIT和PD-1存在可变的共表达。研究表明，肿瘤浸润性CD8+T细胞（CD8+TIL）中CD226与TIGIT或PD-1呈负相关。因此，无论健康供体和癌症患者的T细胞中CD226的表达如何，TIGIT和PD-1并不总是共表达9,55,64。

This raises the question about the regulation of CD226 in CD226 + TIGIT + PD-1- T-cell populations if TIGIT only partially inhibits CD226 activation through competitive binding to PVR. In addition, it is important to determine whether NK cells, which rarely express PD-165, employ a distinct regulatory mechanism for CD226 compared with T cells..

如果TIGIT仅通过与PVR的竞争性结合部分抑制CD226活化，这就提出了CD226在CD226++TIGIT++PD-1-T细胞群中调节CD226的问题。此外，重要的是要确定与T细胞相比，很少表达PD-165的NK细胞是否对CD226具有独特的调节机制。。

More importantly, it remains unclear whether PD-1 binding to PD-L1 alone can trigger CD226 inhibition or is a sequential event following TIGIT-PVR binding-mediated CD226 regulation. This is particularly important for combination therapy targeting the PD-(L)1 and TIGIT pathways, as the co-expression of PD-L1 and PVR by tumors might be necessary for this sequential event.

更重要的是，尚不清楚PD-1单独与PD-L1结合是否可以触发CD226抑制，或者是TIGIT-PVR结合介导的CD226调节后的连续事件。。

However, a previous study reported no correlation between PVR and PD-L1 expression in five different cohorts of patients with lung adenocarcinoma38. Finally, the roles of other TIGIT family members, especially those related to CD226 regulation, remain elusive. While it remains controversial whether CD96 has costimulatory or inhibitory activity, CD112R is known as a co-inhibitory receptor that binds to nectin-233.

然而，之前的一项研究报道，在五个不同的肺腺癌患者队列中，PVR和PD-L1表达之间没有相关性38。。虽然CD96是否具有共刺激或抑制活性仍存在争议，但CD112R被称为与nectin-233结合的共抑制受体。

Therefore, understanding whether CD112R also requires PD-1 to inhibit CD226 and how it interacts with TIGIT is necessary to elucidate the broader regulatory network involving CD226..

因此，了解CD112R是否也需要PD-1抑制CD226以及它如何与TIGIT相互作用对于阐明涉及CD226的更广泛的调控网络是必要的。。

CD226 in tumor immunityCD8 + T-cell regulationThe role of CD226 in modulating CD8 + T-cell-mediated antitumor responses has been assessed in various mouse tumor models. CD226-deficient mice presented increased tumor development and mortality after transplantation of Meth A, 3-methylcholanthrene (MCA)-induced fibrosarcoma, 7,12-dimethylbenz[a]anthracene (DMBA)-induced papilloma tumor cells or CT2610,66.

CD226在肿瘤免疫中的CD8+T细胞调节已经在各种小鼠肿瘤模型中评估了CD226在调节CD8+T细胞介导的抗肿瘤反应中的作用。CD226缺陷小鼠在移植甲氧基，3-甲基胆蒽（MCA）诱导的纤维肉瘤，7,12-二甲基苯并蒽（DMBA）诱导的乳头状瘤肿瘤细胞或CT2610,66后表现出增加的肿瘤发展和死亡率。

In addition, the growth of implanted MC38-OVA tumor cells was not controlled in CD226-deficient mice57. In an adoptive transfer model of Pmel-1-CD8 + T cells into melanoma-bearing mice, mice given CD226-deficient Pmel-1-CD8 + T cells presented a decreased survival rate compared with that of mice given WT Pmel-1-CD8 + T cells67.

此外，在CD226缺陷小鼠中，植入的MC38-OVA肿瘤细胞的生长不受控制57。。

CD226 deficiency affects the antitumor efficacy of anti-PD-1 or anti-TIGIT antibodies in B16K1- or CT26-bearing mice10,68. This effect was also observed in mouse tumor model studies in which anti-CD226 antagonist antibodies were used to block the interaction between CD226 and PVR. While CD226 blockade alone did not alter tumor growth or mortality in various mouse tumor models, including CT26, RENCA or lung metastasis models69,70,71, co-treatment of anti-CD226 mAb with anti-TIGIT and anti-PD-L1 mAbs or anti-PD-1 and anti-GITR mAbs inhibited antitumor responses mediated by the combined treatment with those mAbs.

CD226缺陷影响抗PD-1或抗TIGIT抗体在携带B16K1或CT26的小鼠中的抗肿瘤功效10,68。在小鼠肿瘤模型研究中也观察到这种效应，其中使用抗CD226拮抗剂抗体阻断CD226和PVR之间的相互作用。虽然单独使用CD226阻断剂不会改变各种小鼠肿瘤模型（包括CT26，RENCA或肺转移模型）中的肿瘤生长或死亡率69,70,71，但抗CD226 mAb与抗TIGIT和抗PD-L1 mAb或抗PD-1和抗GITR mAb的联合治疗抑制了由这些mAb联合治疗介导的抗肿瘤反应。

Immune monitoring studies with TILs revealed that CD226 blockade reversed the increased infiltration and cytokine production of CD8 + T cells induced by the combination treatment69,71. The discrepant effects of genetic deletion of CD226 and blockade of CD226 with an antibody on tumor control should be further assessed.

TIL的免疫监测研究表明，CD226阻断逆转了联合治疗诱导的CD8+T细胞浸润和细胞因子产生的增加69,71。应进一步评估CD226基因缺失和抗体阻断CD226对肿瘤控制的不同影响。

Previous studies reported no alterations in T-cell development or homeostasis in CD226-deficient mice under steady-state cond.

先前的研究报道，在稳态条件下，CD226缺陷小鼠的T细胞发育或体内平衡没有改变。

The impact of CD226 downregulation on CD8 + T-cell responses

CD226下调对CD8+T细胞反应的影响

Similar to T-cell adhesion molecules, CD226 is also constitutively expressed on both naïve and memory T cells at varying expression levels9,68. There are three different CD226 expression levels (CD226hi, CD226int, and CD226lo) in the memory subset, and naïve T cells harbor CD226int and CD226lo populations under steady-state conditions.

与T细胞粘附分子类似，CD226也在幼稚和记忆T细胞上以不同的表达水平组成性表达9,68。记忆子集中有三种不同的CD226表达水平（CD226hi，CD226int和CD226lo），并且幼稚T细胞在稳态条件下具有CD226int和CD226lo群体。

CD226loCD8 + T cells within tumors are more abundant than those in normal tissues or peripheral blood in patients with non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), multiple myeloma (MM), colorectal cancer (CRC) and CRC liver metastases9,68,73. Compared with CD226hiCD8 + TILs, CD226loCD8 + TILs show reduced cytokine production and proliferative capacity9,68,73.

在非小细胞肺癌（NSCLC），肾细胞癌（RCC），多发性骨髓瘤（MM），结直肠癌（CRC）和CRC肝转移患者中，肿瘤内CD226loCD8+T细胞比正常组织或外周血中的CD226loCD8+T细胞更丰富9,68,73。与CD226hiCD8+TILs相比，CD226loCD8+TILs显示细胞因子产生和增殖能力降低9,68,73。

Similar functional defects in CD8+TILs with CD226 downregulation have also been observed in various mouse tumor models9,67,68,74. Furthermore, downregulation of CD226 is often accompanied by upregulation of coinhibitory immune checkpoint receptors such as TIGIT, PD-1, Tim-3, and LAG-3 in CD8+TILs from patients with RCC, CRC, NSCLC, squamous cell carcinoma (SCC), and melanoma, which can be considered phenotypic characteristics of exhausted T cells9,55,64.

在各种小鼠肿瘤模型中也观察到CD226下调的CD8+TIL中类似的功能缺陷9,67,68,74。此外，CD226的下调通常伴随着来自RCC，CRC，NSCLC，鳞状细胞癌（SCC）和黑色素瘤患者的CD8+TIL中的共抑制性免疫检查点受体如TIGIT，PD-1，Tim-3和LAG-3的上调，这可以被认为是耗尽的T细胞的表型特征9,55,64。

However, some reports have shown no inverse correlation between CD226 and coinhibitory receptor expression in CD8 + TILs67,68,73. This disparity may be due to the heterogeneity of the population represented by CD226 downregulation or the varied status of T-cell differentiation depending on the tumor burden or variations in tumor types.

然而，一些报道显示CD226与CD8+TILs67,68,73中共抑制受体表达之间没有负相关。这种差异可能是由于CD226下调所代表的群体的异质性或T细胞分化的不同状态，这取决于肿瘤负荷或肿瘤类型的变化。

Indeed, transcriptome analysis by single-cell RNA sequencing (scRNA-seq) in CD226loCD8 + TILs did not reveal a consistent definition of a specific subset, such as exhausted T cells67. Compared with CD226hiCD8 + TILs, which present enriched gene expression profiles of T-cell activati.

事实上，通过CD226loCD8+ TILs中的单细胞RNA测序（scRNA-seq）进行的转录组分析并未揭示特定子集的一致定义，例如耗尽的T细胞67。与CD226hiCD8+TILs相比，CD226hiCD8+TILs具有丰富的T细胞活化基因表达谱。

Treg cell regulationTregs contribute to immune homeostasis by controlling autoimmune reactions and promoting self-tolerance in tissues76. Several studies have suggested that CD226 plays a suppressive role in Treg function in mouse models of inflammation and autoimmune disease77,78. For example, conditional knockout of CD226 specifically in Tregs decreased insulitis and delayed the onset of diabetes in female NOD mice79.

Treg细胞调节因子通过控制自身免疫反应和促进组织中的自我耐受来促进免疫稳态76。一些研究表明，CD226在炎症和自身免疫性疾病小鼠模型中对Treg功能起抑制作用77,78。例如，特异性在Tregs中条件性敲除CD226可减少胰岛炎并延缓女性NOD小鼠糖尿病的发作79。

CD226 deficiency maintains Treg function during acute graft-versus-host disease (GvHD)80. However, a recent study employing Treg-specific CD226 knockout mice revealed that the deletion of CD226 exacerbated the severity of GvHD and inflammatory bowel disease in animal models. The impairment of inhibitory activity in CD226 knockout Tregs has been attributed to the heightened plasticity of Tregs, which causes them to adopt a Th1-like phenotype and consequently lose their ability to suppress inflammation81,82.

CD226缺陷在急性移植物抗宿主病（GvHD）80期间维持Treg功能。然而，最近一项使用Treg特异性CD226基因敲除小鼠的研究表明，CD226的缺失加剧了动物模型中GvHD和炎症性肠病的严重程度。CD226敲除Tregs的抑制活性受损归因于Tregs的可塑性增强，这导致它们采用Th1样表型，从而失去抑制炎症的能力81,82。

The uncertainty surrounding CD226-mediated Treg regulation may arise from variations in the expression of CD226 and TIGIT under different circumstances, as well as their functional interactions. TIGIT is highly expressed on Tregs and contributes to their immune-suppressive function83,84. TIGIT has been shown to restrict the PI3K-AKT pathway, thereby impeding the acquisition of a Th1 cell-like phenotype83.

围绕CD226介导的Treg调节的不确定性可能来自不同情况下CD226和TIGIT表达的变化以及它们的功能相互作用。。TIGIT已被证明可以限制PI3K-AKT途径，从而阻碍Th1细胞样表型的获得83。

In inflammatory environments, CD226 competes with TIGIT for binding to the PVR ligand80. Conversely, within the tumor microenvironment, Tregs exhibit reduced expression of CD22685. Particularly in melanoma, human Tregs display elevated TIGIT expression and decreased CD226 expression. This leads to increased TIGIT signaling, which suppresses the PI3K-AKT pathway and enhances the suppressive functions of Tregs.

在炎症环境中，CD226与TIGIT竞争结合PVR配体80。相反，在肿瘤微环境中，Tregs表现出CD22685的表达降低。特别是在黑色素瘤中，人Tregs显示出升高的TIGIT表达和降低的CD226表达。这导致增加的TIGIT信号传导，其抑制PI3K-AKT途径并增强Tregs的抑制功能。

Human Tregs display a considerable degree .

人类Tregs显示出相当大的程度。

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Download referencesFundingThis work was supported by an intramural grant from KIST to Y.P., as well as grants from the National Research Foundation of Korea (NRF) funded by the Korea government (MSIT) (NRF-2020M3A9G7103935 and RS-2024-00338729 to H.J. and RS-2024-00337093 to Y.P.). All of the figures were created using Biorender.com.Author informationAuthors and AffiliationsChemical and Biological Integrative Research Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, South KoreaYunju Jo, Hye-In Sim & Yoon ParkDepartment of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South KoreaBohwan Yun & Hyung-seung JinAuthorsYunju JoView author publicationsYou can also search for this author in.

下载参考文献资助这项工作得到了KIST向Y.P.提供的校内资助，以及韩国政府（MSIT）资助的韩国国家研究基金会（NRF）的资助（NRF-2020M3A9G7103935和RS-2024-00338729授予H.J.和RS-2024-00337093授予Y.P.）。所有这些数字都是使用Biorender.com.Author informationAuthors和AffiliationsChemical and Biological integration Research Center，生物医学研究所，韩国科学技术研究所（KIST），首尔，韩国Yunju Jo，Hye In Sim＆Yoon Park融合医学系，Asan生命科学研究所，Asan医学中心，蔚山大学医学院，首尔，韩国Bohwan Yun＆Hyung seung Jin作者Yunju JoView作者出版物您也可以在中搜索这位作者。

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Reprints and permissionsAbout this articleCite this articleJo, Y., Sim, HI., Yun, B. et al. Revisiting T-cell adhesion molecules as potential targets for cancer immunotherapy: CD226 and CD2.

转载和许可本文引用本文Jo，Y.，Sim，HI。，Yun，B.等人重新审视T细胞粘附分子作为癌症免疫治疗的潜在靶点：CD226和CD2。

Exp Mol Med (2024). https://doi.org/10.1038/s12276-024-01317-9Download citationReceived: 30 April 2024Revised: 26 June 2024Accepted: 04 July 2024Published: 01 October 2024DOI: https://doi.org/10.1038/s12276-024-01317-9Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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