PO.TB10.19 · 肿瘤生物学
CD155结合肽增强T细胞的抗肿瘤活性及溶解肽在结肠肿瘤中的细胞毒性活性
CD155- binding peptide enhances antitumor activity of T cells and cytotoxic activity of a lytic peptide in colon tumor
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
CD155是一种免疫球蛋白样蛋白，在大多数肿瘤细胞中过表达，并促进肿瘤细胞的增殖、粘附和迁移/侵袭。CD155有多种免疫检查点受体，包括CD226、TIGIT、CD96、CD112R（PVRIG）和KIR2DL5。这些配体以不同的亲和力结合PVR样蛋白受体，从而发挥免疫激活或免疫抑制功能。CD155与TIGIT结合的亲和力远高于其与CD96或CD226的结合。此外，CD155的免疫抑制靶点TIGIT、CD96与免疫激活靶点CD226竞争，以抑制免疫系统激活。因此，TIGIT通过阻止CD226介导的共刺激，对免疫细胞发挥免疫抑制作用。结肠肿瘤中CD155的上调与患者不良结局相关，这凸显了其作为治疗靶点的潜力。利用噬菌体展示肽库，我们鉴定出一种以高亲和力结合CD155的肽（CD155pep）。在CT26结肠肿瘤细胞与CD8+ T细胞共培养期间用CD155pep处理，下调了肿瘤细胞的CD155表达，并增强了T细胞的抗肿瘤活性，包括granzyme B、interferon-gamma和tumor necrosis factor-alpha的释放，以及肿瘤细胞裂解的增加。此外，在肿瘤相关巨噬细胞与CD8+ T细胞共培养期间用CD155pep处理，减少了抗炎性IL-10的产生，同时增加了巨噬细胞促炎性IL-12的分泌。此外，CD155pep连接的溶解肽对肿瘤细胞相较于正常细胞表现出选择性毒性，并抑制了小鼠体内的肿瘤生长。这些结果凸显了CD155pep和CD155pep连接的溶解肽用于CD155高表达肿瘤靶向治疗的治疗潜力。
查看英文原文 English abstract
CD155 is an immunoglobulin-like protein overexpressed in most tumor cells and promotes the proliferation, adhesion, and migration/invasion of tumor cells. CD155 has multiple immune checkpoint receptors, including CD226, TIGIT, CD96, CD112R (PVRIG) and KIR2DL5. These ligands bind with different affinities to PVR-like protein receptors, thus exerting immune-activating or immunosuppressive functions.CD155 binds to TIGIT with far higher affinity than binds to CD96 or CD226. Moreover, the CD155 immunosuppressive target TIGIT, CD96 competes with the immune activation target CD226 to inhibit immune system activation. As a result, TIGIT exerts an immunosuppressive impact on immune cells by preventing CD226-mediated co-stimulation. Upregulation of CD155 in colon tumor is associated with poor patient outcomes, which highlights its potential as therapeutic target. Using a phage-displayed peptide library, we identified a peptide that binds CD155 with a high affinity (CD155pep). Treatment of CT26 colon tumor cells with CD155pep during co-cultures with CD8+ T cells down-regulated CD155 expression of the tumor cells and enhanced antitumor activity of T cells, including the release of granzyme B, interferon-gamma, and tumor necrosis factor-alpha, and the increase of tumor cells lysis. In addition, treatment of tumor-associated macrophages with CD155pep during co-cultures with CD8+ T cells decreased anti-inflammatory IL-10 production while increasing pro-inflammatory IL-12 secretion of macrophages. Furthermore, CD155pep-linked lytic peptide showed a selective toxicity in tumor cells over normal cells and inhibited tumor growth in mice. These results highlight the therapeutic potential of CD155pep and CD155pep-linked lytic peptide for targeted therapy of CD155-high tumors.
利益披露 Disclosure
G. Gowri Rangaswamy, None.