Abstract 2781: Mechanism study of surufatinib on the optimized strategy of AG plus PD-1 antibody treatment in pancreatic cancer
Authors: Gao Song , Zhu Wenbo , Guo Xiaofan , Liang Yuexiang , Wang Hongwei , Xu Peijun , Song Yuning , Hao Jihui , Wen Shaoshi , Lv Xing , Zhou Jiancai 
Published: April 2023

Abstract
Background: Gemcitabine combined with albumin-bound paclitaxel (AG) is the standard treatment for pancreatic cancer. However, it provides no benefit after combined AG with PD-1 antibody, which needs to be optimized urgently. Surufatinib (SUR) is a novel small-molecule inhibitor that observably inhibits VEGFR 1, 2, 3, fibroblast growth factor receptor 1 (FGFR 1), and colony stimulating factor-1 receptor (CSF-1R), which simultaneously shows anti-angiogenic activity and immune microenvironment activation. Herein, we aimed to explore the synergistic effect and related mechanism of SUR plus AG and PD-1 antibody (SAP) regimen.
Methods: Surgical tumor specimens were collected and analyzed using single-cell sequencing and immunohistochemistry technology. Orthotopic transplantation mice model of pancreatic cancer and co-culture system of pancreatic cancer cells and tumor-associated macrophages (TAMs) were successively established to reveal the potential molecular mechanism of SUR in optimizing the effects of AG plus PD-1 antibody, by western blot, immunofluorescence and ubiquitination experiments.
Results: Tumor CSF-1 levels were markedly promoted in pancreatic cancer patients after the treatment of gemcitabine, while an increased infiltration of M2 polarized TAMs (M2-TAMs) was induced. A time-dependent upregulation of M2-TAMs infiltration and PD-L1 expression were also observed after the treatment of AG regimen, which might interfere the therapeutic benefits of AG plus PD-1. In co-culture system, tumor PD-L1 expression levels were distinctly down-regulated after the treatment of SAP regimen, while the decreased infiltration of M2-TAMs was observed. In pancreatic cancer cell, PD-L1 protein synthesis were obviously inhibited by SUR, instead of PD-L1 mRNA expression. After the pancreatic cancer cells pretreated with cycloheximide to inhibit protein synthesis, the half-life period of PD-L1 was ulteriorly reduced by SUR. Inversely, the inhibitory action of SUR on PD-L1 expression was reversed by proteasome inhibitor PS-341, rather than lysosomal inhibitor chloroquine. As a result, it indicated that the protein stability of PD-L1 might interfered by SUR via ubiquitin-proteasome pathway. Particularly, when compared with AG plus PD-1 antibody treatment in tumor-bearing model, SAP regimen significantly down-regulated the expression levels of CSF1R, CD163 and PD-L1, and inhibited tumor growth by promoting tumor cell apoptosis and improving the tumor immune microenvironment.
Conclusions: Forceful evidence supported that PD-L1 expression could be interfered by surufatinib via ubiquitin-proteasome pathway and M2-TAMs regulation. Herein, additional administration of surufatinib might improve the immunosuppression and drug resistance caused by AG, and increase the curative effect of AG plus PD-1 antibody treatment in clinical practice.
Citation Format: Song Gao, Wenbo Zhu, Xiaofan Guo, Yuexiang Liang, Hongwei Wang, Peijun Xu, Yuning Song, Jihui Hao, Shaoshi Wen, Xing Lv, Jiancai Zhou. Mechanism study of surufatinib on the optimized strategy of AG plus PD-1 antibody treatment in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2781.