Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
Int J Mol Sci. 2022 Jun 9;23(12):6442. doi: 10.3390/ijms23126442.
Pancreatic ductal adenocarcinoma (PDAC) has up to half the tumor mass of tumor-associated myeloid cells. Myeloid innate immune cells play important roles in regulating cancer cell recognition and tumor growth. PDAC cells often mold myeloid cells into pro-tumoral state to fuel cancer growth and induce immune suppression. However, how tumor cells educate the innate immune responses remains largely unknown. In this study, we used four different human PDAC cell lines (PANC1, BxPC3, AsPC1, and CFPAC1) to establish the zebrafish xenograft model and investigated the interaction between pancreatic cancer and innate immune cells. The primary tumor-derived cancer cells PANC1 and BxPC3 activated innate immune anti-tumoral responses efficiently, while cancer cells from metastatic tissues AsPC1 and CFPAC1 induced an innate immune suppression and educated innate immune cells towards pro-tumoral state. Chemical conversion of innate immune cells to anti-tumoral state inhibited tumor growth for AsPC1 and CFPAC1. Moreover, genetic and pharmacological inhibition of macrophages also significantly reduced tumor growth, supporting the important roles of macrophages in innate immune suppression. REG4 expression is high in AsPC1 and CFPAC1. Knockdown of REG4 induced innate immune activation and reduced tumor growth in the xenografts, indicating that REG4 is a beneficial target for PDAC therapy. Our study provides a fast in-vivo model to study PDAC-innate immune interaction and their plasticity that could be used to study the related mechanism as well as identify new drugs to enhance immunotherapy.
胰腺导管腺癌 (PDAC) 的肿瘤相关髓系细胞数量可达肿瘤质量的一半。髓系固有免疫细胞在调节癌细胞识别和肿瘤生长方面发挥着重要作用。PDAC 细胞常将髓系细胞塑造成促肿瘤状态，以促进癌症生长并诱导免疫抑制。然而，肿瘤细胞如何教育固有免疫反应在很大程度上仍然未知。在这项研究中，我们使用了四种不同的人 PDAC 细胞系 (PANC1、BxPC3、AsPC1 和 CFPAC1) 来建立斑马鱼异种移植模型，并研究了胰腺癌与固有免疫细胞之间的相互作用。原代肿瘤衍生的癌细胞 PANC1 和 BxPC3 有效地激活了固有免疫抗肿瘤反应，而来自转移组织的癌细胞 AsPC1 和 CFPAC1 则诱导了固有免疫抑制，并将固有免疫细胞教育为促肿瘤状态。将固有免疫细胞化学转化为抗肿瘤状态可抑制 AsPC1 和 CFPAC1 的肿瘤生长。此外，巨噬细胞的基因和药理学抑制也显著减少了肿瘤生长，支持巨噬细胞在固有免疫抑制中的重要作用。REG4 在 AsPC1 和 CFPAC1 中的表达水平较高。REG4 的敲低诱导了固有免疫的激活，并减少了异种移植物中的肿瘤生长，表明 REG4 是 PDAC 治疗的一个有益靶点。我们的研究提供了一种快速的体内模型来研究 PDAC-固有免疫相互作用及其可塑性，可用于研究相关机制并确定新的药物来增强免疫治疗。
