Cato Research, Durham, North Carolina.
Department of Medicine, Georgetown University, Washington, District of Columbia.
Am J Physiol Gastrointest Liver Physiol. 2019 Nov 1;317(5):G682-G693. doi: 10.1152/ajpgi.00145.2019. Epub 2019 Aug 21.
Growth of pancreatic cancer is stimulated by gastrin in both a paracrine and an autocrine fashion. Traditional therapies have not significantly improved survival, and recently pancreatic cancer has been deemed a "cold" tumor due to its poor response to immunotherapy. Strategies to improve survival of pancreatic cancer are desperately needed. In the current investigation, we studied the effects of an anti-gastrin cancer vaccine, polyclonal antibody stimulator (PAS; formerly called G17DT and Gastrimmune), used alone or in combination with a programmed cell death receptor (PD)-1 immune checkpoint antibody on pancreatic cancer growth, metastases, and the tumor microenvironment (TME). Immune-competent female C57BL/6 mice bearing syngeneic orthotopic murine pancreatic cancer treated with PAS had significantly smaller tumors and fewer metastases. Examination of the TME demonstrated decreased fibrosis with fewer M2 and more M1 tumor-associated macrophages. Expression of the gene was significantly increased and expression of the gene was decreased compared with controls. Mice treated with PAS or the combination of PAS and PD-1 antibody exhibited significantly less tumor expression of phospho-paxillin, the focal adhesion protein β-catenin, and matrix metalloproteinase-7. This study suggests that inhibition of the cancer-promoting effects of gastrin in pancreatic cancer can decrease metastases by altering the TME and decreasing pathways that activate the epithelial mesenchymal transition. The PAS vaccine appears to change the TME, making it more susceptible to therapy with an immune checkpoint antibody. This novel combination of two immunotherapies may improve survival of pancreatic cancer by decreasing both tumor growth and metastasis formation. Survival from advanced pancreatic cancer is poor, in part due to dense fibrosis of the tumor microenvironment, increased number of M2-polarized macrophages that promote angiogenesis and invasion, and lack of "target-specific" therapy. Herein, we report that a tumor vaccine that selectively targets gastrin decreases pancreatic cancer growth and metastases. Furthermore, the gastrin vaccine polyclonal antibody stimulator alters the tumor microenvironment rendering it more responsive to immunotherapy with a programmed cell death receptor-1 immune checkpoint antibody.
胃泌素通过旁分泌和自分泌方式刺激胰腺癌的生长。传统疗法并未显著改善患者的生存状况，最近由于对免疫疗法的反应较差，胰腺癌被认为是一种“冷”肿瘤。迫切需要提高胰腺癌患者的生存率。在当前的研究中，我们研究了抗胃泌素癌症疫苗多克隆抗体刺激剂（PAS；以前称为 G17DT 和 Gastrimmune）单独或与程序性细胞死亡受体（PD）-1 免疫检查点抗体联合使用对胰腺癌细胞生长、转移和肿瘤微环境（TME）的影响。用 PAS 治疗携带同源原位鼠胰腺癌的免疫功能正常的雌性 C57BL/6 小鼠的肿瘤明显较小，转移灶较少。对 TME 的检查表明，纤维化减少，M2 型肿瘤相关巨噬细胞减少，M1 型增加。与对照组相比，基因的表达显著增加，基因的表达减少。与对照组相比，用 PAS 或 PAS 和 PD-1 抗体联合治疗的小鼠肿瘤中磷酸化斑联蛋白、黏着斑蛋白 β-连环蛋白和基质金属蛋白酶-7 的表达明显减少。本研究表明，抑制胃泌素在胰腺癌中的促癌作用可以通过改变 TME 并减少激活上皮间质转化的途径来减少转移。PAS 疫苗似乎改变了 TME，使其更容易接受免疫检查点抗体的治疗。两种免疫疗法的这种新组合可能通过减少肿瘤生长和转移形成来提高胰腺癌的生存率。晚期胰腺癌的生存率较差，部分原因是肿瘤微环境的纤维化程度高，促进血管生成和侵袭的 M2 极化巨噬细胞数量增加，以及缺乏“靶向特异性”治疗。在此，我们报告称，一种选择性靶向胃泌素的肿瘤疫苗可降低胰腺癌的生长和转移。此外，胃泌素疫苗多克隆抗体刺激剂改变了肿瘤微环境，使其对程序性细胞死亡受体-1 免疫检查点抗体的免疫治疗更敏感。
