肿瘤相关成纤维细胞在PD-1单抗治疗胰腺导管腺癌中的作用及机制

Programmed Death 1 (PD-1) monoantibody has showed good effect in treating patients with gastric or colorectal cancer. However, it has no significant effect on pancreatic ductal adenocarcinoma (PDAC), and the mechanism underlying is still unclear. Cancer associated fibroblasts (CAFs) which are abundant in PADC are thought to be related to poor therapeutic efficacy of PD-1. In the pilot study, CAFs secreted more Wnt16B when stimulated by PD-1 monoantibody in PDAC, and the expression of Wnt16B has been proved to be positively correlated with the proportion of CD8+PD-1+T cells. In addition, the expression of PD-1 in CD8+ T cells was upregulated by Wnt16B in vitro. Based on the findings of our pilot research, this study attempts to investigate the role and potential mechanisms of CAFs and their secreted Wnt16B in the resistance to PD-1 monoantibody by PDAC . The results may not only reveal the causes of the failure of PD-1 monoantibody in treating PADC, but also provide theoretical basis for Wnt16B inhibitor combined with PD-1 monoantibody in the treatment of PDAC. It may also provide new insight in the field of immunotherapy of PDAC.

PD-1单抗在胃癌、结直肠癌等肿瘤治疗中取得了良好的效果，但对胰腺导管腺癌（PDAC）却无明显疗效，其机制不明。PDAC中大量存在的肿瘤相关成纤维细胞（CAFs）被认为与PD-1单抗治疗效果不佳有关。课题组前期研究发现PD-1单抗能刺激CAFs分泌更多的Wnt16B，而Wnt16B的表达量又与CD8+PD-1+T细胞比例呈正相关，体外实验也证实Wnt16B能够上调CD8+T细胞中PD-1的表达。本课题拟在前期实验基础上，通过体外细胞和体内动物实验研究CAFs及其分泌的Wnt16B在PDAC对PD-1单抗耐药中发挥的作用，并进一步探索其中的机制。研究结果不仅可以揭示PD-1单抗治疗PDAC失败的原因，还可以为抑制Wnt16B联合PD-1单抗治疗PDAC提供理论依据，有望给PDAC的免疫治疗开辟一个新的思路。