Targeting PD-1/PD-L1 is only effective in ∼20% of lung cancer patients, but determinants of this response are poorly defined. We previously observed differential responses of two murine K-Ras-mutant lung cancer cell lines to anti-PD-1 therapy: CMT167 tumors were eliminated, whereas Lewis Lung Carcinoma (LLC) tumors were resistant. The goal of this study was to define mechanism(s) mediating this difference. RNA sequencing analysis of cancer cells recovered from lung tumors revealed that CMT167 cells induced an IFNγ signature that was blunted in LLC cells. Silencing Ifngr1 in CMT167 resulted in tumors resistant to IFNγ and anti-PD-1 therapy. Conversely, LLC cells had high basal expression of SOCS1, an inhibitor of IFNγ. Silencing Socs1 increased response to IFNγ in vitro and sensitized tumors to anti-PD-1. This was associated with a reshaped tumor microenvironment, characterized by enhanced T cell infiltration and enrichment of PD-L1^hi myeloid cells. These studies demonstrate that targeted enhancement of tumor-intrinsic IFNγ signaling can induce a cascade of changes associated with increased therapeutic vulnerability.

中文翻译：

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对IFNγ的肿瘤内源性反应可塑造NSCLC中的肿瘤微环境和抗PD-1反应。

靶向PD-1 / PD-L1仅在约20％的肺癌患者中有效，但对这种反应的决定因素定义不清。我们先前观察到了两种鼠类K-Ras突变型肺癌细胞系对PD-1疗法的不同反应：消除了CMT167肿瘤，而刘易斯肺癌（LLC）肿瘤具有耐药性。这项研究的目的是确定介导这种差异的机制。从肺部肿瘤中回收的癌细胞的RNA测序分析表明，CMT167细胞诱导了IFNγ标记，该标记在LLC细胞中变钝了。使CMT167中的Ifngr1沉默会导致对IFNγ和抗PD-1治疗具有抵抗力的肿瘤。相反，LLC细胞具有高度基础表达的SOCS1，即IFNγ的抑制剂。沉默的社会1增加了对IFNγ的体外反应，并使肿瘤对抗PD-1敏感。这与重塑的肿瘤微环境有关，其特征在于增强的T细胞浸润和PD-L1 ^hi髓样细胞的富集。这些研究表明，肿瘤内源性IFNγ信号的靶向增强可以诱导与治疗易感性增加相关的级联变化。