肿瘤细胞治疗研究
英文原题：Stromal modifying CHST15 siRNA enhances antitumor effect synergistically with anti-PD-1 immune checkpoint antibody in murine pancreatic cancer.
Stromal modifying CHST15 siRNA enhances antitumor effect synergistically with anti-PD-1 immune checkpoint antibody in murine pancreatic cancer.
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肿瘤基质重塑是免疫检查点抑制剂（ICI）的障碍。针对碳水化合物磺基转移酶15（CHST15）的基质修饰小干扰RNA（siRNA）近期被证明可增强肿瘤浸润性T细胞，但其对ICI抗肿瘤应答的影响尚未被探索。在小鼠胰腺癌KPC和Pan02皮下同种移植肿瘤模型中，小鼠被分为4组进行治疗；（1）对照组，（2）CHST15 siRNA单药治疗，（3）抗程序性死亡受体1（PD-1）单药治疗，（4）CHST15 siRNA与抗PD-1抗体联合治疗。治疗2周后处死小鼠，分别通过KPC模型的免疫组织化学和Pan02模型的流式细胞术评估抗肿瘤效果。在KPC模型中，瘤内注射CHST15 siRNA（0.9-1.0 mg/kg）联合全身性抗PD-1抗体（5 mg/kg）治疗与抗PD-1单药治疗相比，协同且显著抑制了肿瘤生长，并显著增加了肿瘤浸润性CD4+和CD8+ T细胞。在Pan02模型中，CHST15 siRNA与抗PD-1联合治疗与对照组相比显示出抗肿瘤效果，肿瘤坏死面积百分比和肿瘤浸润性T细胞显著增加。
值得注意的是，与抗PD-1单药治疗相比，联合治疗显著减少了Ly6C+Ly6G+粒细胞系髓源性抑制细胞（MDSCs）。本研究证明了全身性抗PD-1抗体与单一基质修饰剂之间的强大协同作用。瘤内注射CHST15 siRNA的联合使用将为触发ICI对这种最难治实体瘤的显著效果提供一种新的治疗选择。
Tumor stromal remodeling is an obstacle for immune checkpoint inhibitors (ICI). A stroma modifying small interfering RNA (siRNA) to carbohydrate sulfotransferase 15 (CHST15) was recently shown to enhance tumor-infiltrating T cells, yet its impact on antitumor response of ICI remains unexplored. In mouse pancreatic cancer KPC and Pan02 subcutaneous syngeneic tumor models, mice were divided into 4 groups for treatment; (1) control, (2) CHST15 siRNA monotherapy, (3) anti-programmed death receptor 1 (PD-1) monotherapy, and (4) combination therapy with CHST15 siRNA and anti-PD-1 antibody.
Mice were sacrificed after 2 week-treatments and anti-tumor effects were evaluated by immunohistochemistry for KPC and flow cytometry for Pan02 model, respectively. In the KPC model, combination treatment with intratumoral CHST15 siRNA (0. 9-1.
0 mg/kg) and systemic anti-PD-1 antibody (5 mg/kg) synergistically and robustly suppressed tumor growth with a significant increase of tumor-infiltrating CD4 + and CD8 + T cells compared to anti-PD-1 monotherapy. In the Pan02 model, combination treatment with CHST15 siRNA and anti-PD-1 showed anti-tumor effect with significant increases in % necrosis area of the tumor, and tumor-infiltrating T cells compared to the control.
Notably, the combination therapy dramatically diminishes Ly6C + Ly6G + granulocytic myeloid-derived suppressor cells (MDSCs) compared to anti-PD-1 monotherapy. The present study demonstrated the robust synergy between systemic anti-PD-1 antibody and a single stroma modifying agent. Combination usage of intratumoral CHST15 siRNA would provide a novel therapeutic option to trigger the remarkable effect of ICI on this most hard-to-treat solid tumor.
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