Department of Anesthesiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Graduate Institute of Oncology,College of Medicine, National Taiwan University, Taipei, Taiwan.
J Immunother Cancer. 2023 Jul;11(7). doi: 10.1136/jitc-2023-006694.
Expression of immune checkpoints in the tumor microenvironment is one mechanism underlying paclitaxel (PTX) chemoresistance. This study aimed to investigate whether the addition of checkpoint blockade to PTX can improve the therapeutic efficacy against apparently disseminated intraperitoneal tumors.
We analyzed the in vivo expression of various immune checkpoints in CD3CD8 cytotoxic T cells from tumor-bearing mice treated with or without PTX and validated the tumor-killing activities of selected checkpoint-expressing T-cell subpopulations ex vivo. The regulation of selected checkpoints was investigated in vitro. The therapeutic effects of inhibition of a targeted checkpoint pathway with antibodies added to PTX therapy were examined.
CD3CD8 T cells expressed with herpes virus entry mediator (HVEM), programmed cell death 1 (PD-1), and T-cell immunoglobulin domain and mucin domain 3 (TIM-3) in tumor-bearing hosts treated with PTX had effective tumoricidal activities. In addition to PTX and cytokines, B and T lymphocyte attenuator (BTLA) or homologous to lymphotoxin, exhibits inducible expression and competes with herpes simplex virus (HSV) glycoprotein D for binding to HVEM, a receptor expressed on T lymphocytes (LIGHT) interacting with HVEM can regulate the expression of PD-1 on CD3CD8 T cells. Interleukin (IL)-15 increased the percentage of HVEMgranzyme B (GZMB) cells among CD3CD8 T cells, which was suppressed by the BTLA/HVEM signal. LIGHT induced the percentage of HVEMGZMB cells but not HVEMGZMB cells among CD3CD8 T cells. Expression of IL-15, BTLA, or LIGHT was detected in CD19 B cells and regulated by damage-associated molecular patterns/Toll-like receptor interactions. In the tumor-bearing hosts treated with PTX, certain proportions of BTLA B or PD-1 T lymphocytes were still noted. When dual inhibition of BTLA and PD-1 was added to PTX, the antitumor effects on intraperitoneally disseminated tumors can be significantly improved.
Dual blockade of BTLA on B cells and PD-1 on cytotoxic T cells may have clinical potential for enhancing the efficacy of PTX in the treatment of tumors with intraperitoneal spread, including epithelial ovarian carcinomas.
肿瘤微环境中免疫检查点的表达是紫杉醇（PTX）化疗耐药的一种机制。本研究旨在探讨在紫杉醇治疗的基础上增加检查点阻断是否能提高对明显播散性腹腔内肿瘤的治疗效果。
我们分析了荷瘤小鼠经紫杉醇治疗后 CD3CD8 细胞毒性 T 细胞中各种免疫检查点的体内表达情况，并验证了选择的表达检查点的 T 细胞亚群的体外杀伤活性。在体外研究了选定检查点的调节。研究了添加抗体抑制靶向检查点途径对紫杉醇治疗效果的影响。
荷瘤宿主经紫杉醇治疗后表达疱疹病毒进入介质（HVEM）、程序性细胞死亡 1（PD-1）和 T 细胞免疫球蛋白和粘蛋白域 3（TIM-3）的 CD3CD8 T 细胞具有有效的肿瘤杀伤活性。除了紫杉醇和细胞因子外，B 和 T 淋巴细胞衰减因子（BTLA）或淋巴毒素同源物，表达可诱导，并与表达于 T 淋巴细胞上的 HVEM 受体竞争结合（LIGHT）与 HVEM 相互作用可调节 CD3CD8 T 细胞上 PD-1 的表达。白细胞介素（IL）-15 增加了 CD3CD8 T 细胞中 HVEM 颗粒酶 B（GZMB）细胞的比例，而 BTLA/HVEM 信号则抑制了 HVEMGZMB 细胞的比例。LIGHT 诱导了 HVEMGZMB 细胞而非 HVEMGZMB 细胞在 CD3CD8 T 细胞中的比例。在荷瘤宿主经紫杉醇治疗后，在 CD19 B 细胞中检测到 IL-15、BTLA 或 LIGHT 的表达，并受损伤相关分子模式/Toll 样受体相互作用的调节。在荷瘤宿主经紫杉醇治疗后，仍观察到一定比例的 BTLA B 或 PD-1 T 淋巴细胞。当 BTLA 和 PD-1 的双重抑制作用被添加到紫杉醇中时，对腹腔内播散肿瘤的抗肿瘤作用可显著提高。
B 细胞上的 BTLA 和细胞毒性 T 细胞上的 PD-1 的双重阻断可能具有增强紫杉醇治疗包括上皮性卵巢癌在内的腹腔内扩散肿瘤的疗效的临床潜力。
