Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China.
Department of Oncology, Shanghai Medical College, Fudan University, 270 Dongan Road, Shanghai, 200032, People's Republic of China.
J Cancer Res Clin Oncol. 2021 Aug;147(8):2209-2222. doi: 10.1007/s00432-021-03633-3. Epub 2021 Apr 23.
Apatinib, an antiangiogenic drug, has shown beneficial effects only in a fraction of advanced gastric cancer (GC) patients. Given the recent success of immunotherapies, combination of apatinib with immune checkpoint inhibitor may provide sustained and potent antitumor responses.
Immunocompetent mice with subcutaneous MFC tumors grown were given a combination of apatinib and anti-PD-L1 antibody therapy. GC tissues from patients undergoing curative resection in China were collected, and the density of HEVs, MSI status and tumor-infiltrated lymphocytes were analyzed by immunohistochemical staining.
Combined apatinib and PD-L1 blockade therapy synergistically delayed tumor growth and increased survival in MFC-bearing immunocompetent mice. The combination therapy promoted antitumor immunity by increasing the ratio of CD8 cytotoxic T cells to Foxp3 Treg cells, the accumulation of CD20 B cells and the Th1/Th2 cytokine ratio (IFN-γ/IL-10). The combination therapy induced the formation of HEVs through activation of LTβR signaling, thus promoting CD8 cytotoxic T cell and CD20 B cell infiltration in tumors. In clinical GC samples, the density of HEVs positively correlated with the intratumoral infiltration of CD8 cytotoxic T cells and CD20 B cells. MSI-high GC showed a higher density of HEVs, CD8 cytotoxic T cells and CD20 B cells than MSS/MSI-low GC. GC patients with high densities of HEVs, CD8 cytotoxic T cells and CD20 B cells had an improved prognosis with superior overall survival.
Combining apatinib with PD-L1 blockade treatment synergistically enhances antitumor immune responses and promotes HEV formation in GC.
抗血管生成药物阿帕替尼仅在一部分晚期胃癌（GC）患者中显示出有益效果。鉴于免疫疗法最近取得的成功，阿帕替尼与免疫检查点抑制剂联合可能提供持续和有效的抗肿瘤反应。
在皮下 MFC 肿瘤生长的免疫功能正常的小鼠中给予阿帕替尼和抗 PD-L1 抗体联合治疗。收集在中国接受根治性切除术的 GC 组织，通过免疫组织化学染色分析 HEV 密度、微卫星不稳定性（MSI）状态和肿瘤浸润淋巴细胞。
联合阿帕替尼和 PD-L1 阻断治疗协同延迟 MFC 荷瘤免疫功能正常小鼠的肿瘤生长并提高存活率。联合治疗通过增加 CD8 细胞毒性 T 细胞与 Foxp3 Treg 细胞的比例、CD20 B 细胞的积累和 Th1/Th2 细胞因子比例（IFN-γ/IL-10）来促进抗肿瘤免疫。联合治疗通过激活 LTβR 信号通路诱导 HEV 的形成，从而促进 CD8 细胞毒性 T 细胞和 CD20 B 细胞在肿瘤中的浸润。在临床 GC 样本中，HEV 的密度与肿瘤内 CD8 细胞毒性 T 细胞和 CD20 B 细胞的浸润呈正相关。MSI-高 GC 比 MSS/MSI-低 GC 显示出更高的 HEV 密度、CD8 细胞毒性 T 细胞和 CD20 B 细胞密度。GC 患者 HEV、CD8 细胞毒性 T 细胞和 CD20 B 细胞密度高，总生存率提高，预后较好。
阿帕替尼联合 PD-L1 阻断治疗协同增强抗肿瘤免疫反应，并促进 GC 中 HEV 的形成。
