MET-Induced CD73 Restrains STING-Mediated Immunogenicity of EGFR-Mutant Lung Cancer.
MET-Induced CD73 Restrains STING-Mediated Immunogenicity of EGFR-Mutant Lung Cancer.
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DOI：
10.1158/0008-5472.can-22-0770
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发表时间：
2022-11-02
期刊：
影响因子：
11.2
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中科院分区：
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免疫疗法在EGFR突变的肺癌患者中显示出有限的疗效。迄今为止，增强EGFR突变肺癌免疫原性的努力尚未成功。在这里，我们发现MET扩增，对第三代EGFR酪氨酸激酶抑制剂（TKI）耐药的最常见机制，激活肿瘤细胞STING，这是一种新出现的癌症免疫原性决定因素。然而，STING活化受到外核苷酶CD 73的抑制，外核苷酶CD 73在MET扩增的EGFR TKI抗性细胞中诱导。系统的基因组分析和细胞系研究证实了MET扩增和MET活化的肺癌背景下CD 73的上调，这取决于FOSL 1的共诱导。培美曲塞（PEM）通常在EGFR-TKI治疗失败后使用，被确定为MET扩增的EGFR TKI耐药细胞中STING依赖性TBK 1-IRF 3-STAT 1信号传导的有效增强剂。然而，PEM治疗也诱导腺苷的产生，这抑制了T细胞的反应性。在同种异体人源化小鼠模型中，CD 73缺失增强了MET扩增的EGFR TKI耐药细胞的免疫原性，并且PEM治疗促进了稳健的应答，无论CD 73状态如何。使用生理抗原识别模型，CD 73的失活显著增加PEM治疗后的抗原特异性CD 8 + T细胞免疫原性。这些数据表明，组合的PEM和CD 73抑制可以在TKI抗性EGFR突变的肺癌中协同肿瘤细胞STING诱导并促进免疫原性。
Immunotherapy has shown limited efficacy in EGFR-mutated lung cancer patients. Efforts to enhance the immunogenicity of EGFR-mutated lung cancer have been unsuccessful to date. Here, we discover that MET amplification, the most common mechanism of resistance to third generation EGFR tyrosine kinase inhibitors (TKI), activates tumor cell STING, an emerging determinant of cancer immunogenicity. However, STING activation was restrained by ectonucleosidase CD73, which is induced in MET-amplified, EGFR TKI-resistant cells. Systematic genomic analyses and cell line studies confirmed upregulation of CD73 in MET-amplified and MET-activated lung cancer contexts, which depends on co-induction of FOSL1. Pemetrexed (PEM), which is commonly used following EGFR-TKI treatment failure, was identified as effective potentiator of STING-dependent TBK1-IRF3-STAT1 signaling in MET-amplified, EGFR TKI-resistant cells. However, PEM treatment also induced adenosine production, which inhibited T-cell responsiveness. In an allogenic humanized mouse models, CD73 deletion enhanced immunogenicity of MET-amplified, EGFR TKI-resistant cells, and PEM treatment promoted robust responses regardless of CD73 status. Using a physiologic antigen recognition model, inactivation of CD73 significantly increased antigen-specific CD8+ T-cell immunogenicity following PEM treatment. These data reveal that combined PEM and CD73 inhibition can co-opt tumor cell STING induction in TKI resistant EGFR-mutated lung cancers and promote immunogenicity.