Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan.
Department of Hepatopancreatobiliary Surgery, Shengli Clinical Medical College of Fujian Medical University, Fuzhou.
Int J Surg. 2024 May 1;110(5):2679-2691. doi: 10.1097/JS9.0000000000001226.
Chemotherapy resistance is an important cause of neoadjuvant therapy failure in pancreatic ductal adenocarcinoma (PDAC). BiTP (anti-PD-L1/TGF-β bispecific antibody) is a single antibody that can simultaneously and dually target transforming growth factor-beta (TGF-β) and programmed cell death ligand 1 (PD-L1). We attempted in this study to investigate the efficacy of BiTP in combination with first-line chemotherapy in PDAC.
Preclinical assessments of BiTP plus gemcitabine and nab-paclitaxel were completed through a resectable KPC mouse model (C57BL/6J). Spectral flow cytometry, tissue section staining, enzyme-linked immunosorbent assays, Counting Kit-8, transwell, and Western blot assays were used to investigate the synergistic effects.
BiTP combinatorial chemotherapy in neoadjuvant settings significantly downstaged PDAC tumors, enhanced survival, and had a higher resectability for mice with PDAC. BiTP was high affinity binding to targets and reverse chemotherapy resistance of PDAC cells. The combination overcame immune evasion through reprogramming tumor microenvironment via increasing penetration and function of T cells, natural killer cells, and dendritic cells and decreasing the function of immunosuppression-related cells as regulatory T cells, M2 macrophages, myeloid-derived suppressor cells, and cancer-associated fibroblasts.
Our results suggest that the BiTP combinatorial chemotherapy is a promising neoadjuvant therapy for PDAC.
化疗耐药是胰腺导管腺癌（PDAC）新辅助治疗失败的重要原因。BiTP（抗 PD-L1/TGF-β 双特异性抗体）是一种单克隆抗体，可同时双重靶向转化生长因子-β（TGF-β）和程序性细胞死亡配体 1（PD-L1）。本研究旨在探讨 BiTP 联合一线化疗治疗 PDAC 的疗效。
通过可切除的 KPC 小鼠模型（C57BL/6J）完成 BiTP 联合吉西他滨和 nab-紫杉醇的临床前评估。采用光谱流式细胞术、组织切片染色、酶联免疫吸附试验、细胞计数试剂盒-8、Transwell 和 Western blot 检测来研究协同作用。
新辅助治疗中 BiTP 联合化疗显著降期 PDAC 肿瘤，提高了生存时间，并提高了 PDAC 小鼠的可切除性。BiTP 与靶标具有高亲和力结合，逆转 PDAC 细胞的化疗耐药性。该组合通过增加 T 细胞、自然杀伤细胞和树突状细胞的浸润和功能，减少调节性 T 细胞、M2 巨噬细胞、髓系来源的抑制细胞和癌相关成纤维细胞等免疫抑制相关细胞的功能，从而克服了肿瘤微环境中的免疫逃逸。
我们的结果表明，BiTP 联合化疗是一种有前途的 PDAC 新辅助治疗方法。
