Effect of Systemic or Intraperitoneal Administration of Anti-PD-1 Antibody for Peritoneal Metastases from Gastric Cancer
Effect of Systemic or Intraperitoneal Administration of Anti-PD-1 Antibody for Peritoneal Metastases from Gastric Cancer
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DOI：
10.21873/invivo.12811
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发表时间：
2022-05-01
期刊：
影响因子：
2.3
通讯作者：
Kitayama, Joji
中科院分区：
文献类型：
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作者：
Kumagai, Yuko;Futoh, Yurie;Kitayama, Joji
背景/目的：程序性死亡-1（PD-1）/PD-配体1（PD-L1）阻断疗法广泛用于转移性胃癌（GC）患者的治疗。然而，目前尚不清楚PD-1抗体如何影响与腹膜转移瘤（PM）生长相关的局部免疫。PD-1/PD-L1抑制剂对GC PM的临床疗效尚未明确确定。材料与方法：我们通过体内选择建立了小鼠GC细胞向腹膜的高转移性亚克隆YTNI 6 P，并评估了静脉（IV）或腹膜内（IP）给予抗PD-I抗体对免疫活性小鼠模型中PM的影响。用流式细胞术和免疫组化法检测脾脏和腹膜转移灶中免疫细胞的表型。结果：IP接种YTN 16 P（1 × 10（6））3周后导致多发性肠系膜转移。与同种型对照相比，抗PD-mAb的IV和IP施用使肠系膜转移的数量减少了30%至40%。然而，根据给药途径，未观察到差异。尽管脾细胞表型没有改变，但在抗PD-1 mAb处理的小鼠中，腹膜肿瘤中CD 8（+）T细胞的密度显著增加，而Gr-1（+）髓源性抑制细胞（MDSC）的密度显著降低。结论：PD-1阻断疗法重塑腹膜肿瘤的细胞免疫组成，其可部分抑制来自GC的PM，无论施用途径如何。在化疗方案中加入抗PD-1抗体可能会增强其对PM的抗肿瘤作用，这可能会延长腹膜受累的GC患者的生存期。
Background/Aim: Programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) blockade therapy is widely used for the treatment of patients with metastatic gastric cancer (GC). However, it is unclear how PD-1 antibodies affect the local immunity related to the growth of peritoneal metastases (PM). The clinical efficacy of PD-1/PD-L1 inhibitors against PM from GC has not been clearly determined. Materials and Methods: We established a highly metastatic subclone of murine GC cells to the peritoneum, YTNI6P, by in vivo selection and evaluated the effects of intravenous (IV) or intraperitoneal (IP) administration of anti-PD-I antibody on PM in immunocompetent mice model. Phenotypes of immune cells in the spleen and peritoneal metastatic lesions were determined with flow cytometry and immunohistochemistry. Results: IP inoculation of YTN16P (1x10(6)) resulted in multiple mesenteric metastases after 3 weeks. IV and IP administration of anti-PD-ImAb reduced the number of metastases to the mesentery by 30 similar to 40% compared with isotype controls. However, no differences were observed depending on the route of administration. Although splenocyte phenotypes were not altered, the densities of CD8(+) T cells in peritoneal tumors were significantly increased, whereas those of Gr-1(+) myeloid derived suppressor cells (MDSC) were significantly reduced in mice treated with anti-PD-1 mAb. Conclusion: PD-1 blockade therapy remodels the cellular immune composition of peritoneal tumors, which can partially suppress the PM from GC regardless of the route of administration. Adding anti-PD-1 antibody to chemotherapeutic regimens may enhance their anti-tumor effects against PM, which can lead to the prolongation of survival of patients with GC with peritoneal involvement.