PO.PR02.01 · 预防研究
达比加群酯通过重塑免疫微环境增强抗 CTLA4 抗体在 MyC-CaP 细胞同基因小鼠模型中的抗肿瘤作用
Dabigatran etexilate potentiates the anti-tumor effects of anti-CTLA4 antibody through remodeling the immune microenvironment in a syngeneic mouse model of MyC-CaP cells
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摘要 Abstract
中文摘要
达比加群酯是一种 FDA 批准的凝血酶抑制剂，多年来一直用于治疗癌症患者（包括前列腺癌患者）的静脉血栓栓塞。除抗凝特性外，达比加群酯的抗前列腺癌特性和免疫调节能力在很大程度上仍未得到表征。因此，本研究旨在确定达比加群酯单药及其与抗 CTLA4 抗体联合在 MyC-CaP 细胞同基因小鼠模型中的抗肿瘤作用。荷 MyC-CaP 移植瘤的小鼠每日经口灌胃给予达比加群酯，和/或每隔一天经腹腔注射给予抗 CTLA4 抗体治疗，持续 14 天。在整个治疗期间监测肿瘤体积，之后解剖新鲜肿瘤组织，通过流式细胞术表征肿瘤浸润淋巴细胞（TILs）。达比加群酯与鼠抗 CTLA4 阻断抗体联合可显著增强抗肿瘤疗效，与单用抗 CTLA4 单药治疗相比，肿瘤生长抑制提高了 18%，并显著延长了荷瘤小鼠的总生存期。流式细胞术分析显示，达比加群酯与抗 CTLA4 抗体联合可显著增加效应 T 细胞（Teff）群体，同时减少调节性 T 细胞（Tregs）。值得注意的是，与抗 CTLA4 单药治疗相比，联合组中 granzyme B 阳性的细胞毒性 CD8+ T 细胞增加了 1.6 倍。此外，联合组中粒细胞型髓源性抑制细胞（Gr-MDSCs）显著减少。此外，对肿瘤浸润淋巴细胞的单细胞分析显示，达比加群酯与抗 CTLA4 联合治疗显著增加了细胞毒性自然杀伤（NK）细胞的浸润，同时减少了抑制性和耗竭性 NK 细胞群体。综上所述，我们的数据表明，达比加群酯通过激活细胞毒性 T 细胞和 NK 细胞，同时抑制免疫抑制性 Tregs 和 Gr-MDSCs，增强了抗 CTLA4 治疗的效果。这些结果提示达比加群酯值得作为前列腺癌预防和治疗的新型免疫调节药物进一步研究。
查看英文原文 English abstract
Dabigatran etexilate, an FDA approved thrombin inhibitor, has been used for treatment of venous thromboembolism for many years in cancer patients, including prostate cancer patients. Beyond its anticoagulant properties, the anti-prostate cancer properties and immunomodulatory capacity of dabigatran etexilate remain largely uncharacterized. Therefore, this study aims to determine the anti-tumor effects of dabigatran etexilate alone and its combination with anti-CTLA4 antibody in a syngeneic mouse model of MyC-CaP cells. Mice bearing MyC-CaP xenograft tumors received dabigatran etexilate daily via oral gavage and/or anti-CTLA4 antibody treatments every other day through intraperitoneal injection for 14 days. Tumor volumes were monitored throughout the treatments, after which fresh tumor tissues were dissected for flow cytometric characterization of tumor-infiltrating lymphocytes (TILs). The combination of dabigatran etexilate and murine anti-CTLA4 blocking antibody resulted in significantly enhanced anti-tumor efficacy, achieving 18% greater tumor growth inhibition compared to anti-CTLA4 monotherapy alone, and markedly prolonged overall survival of tumor bearing mice. Flow cytometry analysis revealed that dabigatran etexilate in combination with anti-CTLA4 antibody significantly increased effector T cell (Teff) populations while reducing regulatory T cells (Tregs). Notably, granzyme B-positive cytotoxic CD8+ T cells increased by 1.6 folds in the combination group compared to anti-CTLA4 monotherapy. In addition, granulocytic myeloid-derived suppressor cells (Gr-MDSCs) were significantly reduced in the combination group. Furthermore, single-cell analysis of tumor-infiltrating lymphocytes revealed that dabigatran etexilate and anti-CTLA4 combination therapy markedly increased cytotoxic natural killer (NK) cell infiltration while decreasing suppressive and exhausted NK cell populations. Taken together, our data has shown that dabigatran etexilate potentiates anti-CTLA4 therapy by activating cytotoxic T and NK cells while suppressing immunosuppressive Tregs and Gr-MDSCs. These results suggest that dabigatran etexilate deserves further investigation as a new immunomodulatory agent for prostate cancer prevention and treatment.
利益披露 Disclosure
L. Song, None..
M. Gozon, None..
A. Le, None..
J. Xie, None..
X. Zi, None.