Peng Xiandong, Lee Eunji, Liang Jialu, Colon Tania, Tran Franklin, Choi Byeong H, Dai Wei
Division of Environmental Medicine, Department of Medicine, Grossman School of Medicine, New York University, 341 East 25th Street, New York, NY 10010, USA.
Division of Environmental Medicine, Department of Medicine, Grossman School of Medicine, New York University, 341 East 25th Street, New York, NY 10010, USA.
Transl Oncol. 2025 Jan;51:102167. doi: 10.1016/j.tranon.2024.102167. Epub 2024 Nov 16.
Ras proteins are integral to the mediation of signaling cascades to downstream effectors, regulating a multitude of cellular processes. Mutations within Ras and its associated signaling pathways are implicated in various human pathologies, including inflammatory disorders and malignancies. The immune checkpoint proteins, programmed cell death protein 1 (PD-1) and its ligands PD-L1, along with Indoleamine 2,3-dioxygenase-1 (IDO1), are pivotal in facilitating tumor immune escape. While the influence of oncogenic Ras on PD-L1 expression is extensively documented, the regulatory role of KRas in IDO1 expression remains inadequately understood. In the current study, we demonstrate that IDO1 and PD-L1 expressions are differentially regulated in KRas-mutant cancers. Treatment with the KRas-specific inhibitor, ARS-1620, significantly increased IDO1 expression, which inversely correlated with PD-L1 expression in the KRas-mutant H358 cell line. Notably, IDO1 expression was slightly diminished in KRas-mutant patients with lung and pancreatic ductal adenocarcinomas. Experimental data revealed that IFN-γ induces IDO1 expression; however, this induction is attenuated in the presence of constitutively active KRas. These findings suggest that KRas signaling negatively regulates IDO1 expression while enhancing PD-L1 expression. Moreover, the induction of IDO1 expression following KRas inhibition appears to operate independently of the MAPK pathway. Our results propose that concurrent targeting of KRas and IDO1 could potentiate therapeutic efficacy in KRas-mutant cancers, overcoming resistance to immune checkpoint blockade.
Ras蛋白对于向下游效应器介导信号级联反应至关重要，可调节多种细胞过程。Ras及其相关信号通路中的突变与各种人类疾病有关，包括炎症性疾病和恶性肿瘤。免疫检查点蛋白程序性细胞死亡蛋白1（PD-1）及其配体PD-L1，以及吲哚胺2,3-双加氧酶-1（IDO1），在促进肿瘤免疫逃逸中起关键作用。虽然致癌Ras对PD-L1表达的影响已有大量文献记载，但KRas在IDO1表达中的调节作用仍未得到充分了解。在本研究中，我们证明在KRas突变型癌症中，IDO1和PD-L1的表达受到不同的调节。用KRas特异性抑制剂ARS-1620处理可显著增加IDO1的表达，这与KRas突变型H358细胞系中PD-L1的表达呈负相关。值得注意的是，在患有肺和胰腺导管腺癌的KRas突变患者中，IDO1的表达略有下降。实验数据表明，IFN-γ可诱导IDO1表达；然而，在组成型活性KRas存在的情况下，这种诱导作用会减弱。这些发现表明，KRas信号通路对IDO1的表达起负调节作用，同时增强PD-L1的表达。此外，KRas抑制后IDO1表达的诱导似乎独立于MAPK途径。我们的结果表明，同时靶向KRas和IDO1可能会增强KRas突变型癌症的治疗效果，克服对免疫检查点阻断的耐药性。
