下调和上调
肿瘤微环境
巨噬细胞极化
促炎细胞因子
癌症研究
封锁
细胞因子
免疫系统
酪氨酸激酶抑制剂
医学
受体
化学
免疫学
癌症
巨噬细胞
内科学
炎症
体外
基因
生物化学
作者
Ashten N. Omstead,Michael Paskewicz,Anastasia Gorbunova,Ping Zheng,Madison Salvitti,Rubab Mansoor,P I Reed,Sydne Ballengee,Patrick Wagner,Blair A. Jobe,Ronan J. Kelly,Blair A. Jobe
出处
期刊:Carcinogenesis
[Oxford University Press]
日期:2022-05-12
卷期号:43 (9): 842-850
被引量:13
标识
DOI:10.1093/carcin/bgac043
摘要
Abstract Esophageal adenocarcinoma (EAC) is a leading cause of cancer deaths. Pexidartinib, a multi-gene tyrosine kinase inhibitor, through targeting colony-stimulating factor 1 (CSF-1) receptor (CSF-1R), down modulates macrophage-mediated pro-survival tumor signaling. Previously, CSF-1R inhibitors have successfully shown to enhance antitumor activity of PD-1/PD-L1 inhibitors by suppressing tumor immune evasion, in solid tumors. In this study, we investigated the antitumor activity of pexidartinib alone or in combination with blockade of PD-1 in a de novo EAC rat model. Here, we showed limited toxicity with significant tumor shrinkage in pexidartinib treated animals compared to controls, single agent and in combination with a PD-1 inhibitor, AUNP-12. Suppression of CSF-1/CSF-1R axis resulted in enhanced infiltration of CD3 + CD8 + T cells with reduced M2 macrophage polarization, in the tumor microenvironment (TME). Endpoint tissue gene expression in pexidartinib treated animals demonstrated upregulation of BAX, Cas3, TNFα, IFNγ and IL6 and downregulation of Ki67, IL13, IL10, TGFβ and Arg1 (P < 0.05). Additionally, among the pexidartinib treated animals responders compared to nonresponders demonstrated a significant upregulation of pretreatment CSF-1 gene, confirming that tumor-associated macrophage suppression directly translates to clinical benefit. Moreover, a posttreatment serum cytokine assay exhibited similar systemic trends as the gene expression in the TME, depicting increases in proinflammatory cytokines and decreases in anti-inflammatory cytokines. In conclusion, our study established a promising combinatorial strategy using a CSF-1R inhibitor to overcome resistance to PD-1/PD-L1 axis blockade in an EAC model, providing the rationale for future clinical strategies.
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