Proximity proteome mapping reveals PD-L1-dependent pathways disrupted by anti-PD-L1 antibody specifically in EGFR-mutant lung cancer cells.
Proximity proteome mapping reveals PD-L1-dependent pathways disrupted by anti-PD-L1 antibody specifically in EGFR-mutant lung cancer cells.
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DOI：
10.1186/s12964-023-01084-6
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发表时间：
2023-03-13
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PD-L1是免疫检查点受体PD 1的跨膜配体，已成功靶向激活多种实体瘤（包括非小细胞肺癌（NSCLC））中的抗肿瘤免疫应答。尽管靶向PD-L1的治疗取得了成功，但只有约20%的患者获得了持久的缓解。反应异质性的原因尚不清楚，尽管一些分子亚型（例如，突变型EGF受体肿瘤）通常是不良反应者。尽管PD-L1最好的特征是作为跨膜PD 1配体，但新出现的观点是PD-L1具有独立于激活PD 1信号传导的功能。目前尚不清楚PD-L1的这些细胞内在功能是否在非转化细胞和转化细胞中共享，它们是否在癌症分子亚型之间存在差异，或者它们是否受到抗PD-L1治疗的影响。 在这里，我们使用定量显微镜技术和APEX 2邻近映射来描述PD-L1的行为，并确定PD-L1在人肺上皮细胞中的近端蛋白质组。我们的数据揭示了生长因子对PD-L1再循环的控制是质膜上PD-L1密度急性可逆调节的机制。此外，我们还描述了局限于突变型EGFR细胞的新型PD-L1生物学。抗PD-L1抗体治疗突变型EGFR细胞扰乱细胞固有PD-L1功能，导致细胞迁移减少、EGFR半衰期延长和细胞外囊泡生物发生增加，而抗PD-L1抗体在野生型EGFR细胞中不诱导这些变化。生长因子对PD-L1运输的急性调节通过有助于控制质膜密度，可能有助于调节PD-L1的免疫检查点活性，而抗PD-L1对突变型EGFR细胞的特定作用可能导致抗PD-L1的作用较差EGFR突变肿瘤的PD-L1反应。视频摘要在线版本包含补充材料，可通过10. 1186/s12964-023-01084-6获取。
PD-L1, a transmembrane ligand for immune checkpoint receptor PD1, has been successfully targeted to activate an anti-tumor immune response in a variety of solid tumors, including non-small cell lung cancer (NSCLC). Despite the success of targeting PD-L1, only about 20% of patients achieve a durable response. The reasons for the heterogeneity in response are not understood, although some molecular subtypes (e.g., mutant EGF receptor tumors) are generally poor responders. Although PD-L1 is best characterized as a transmembrane PD1 ligand, the emerging view is that PD-L1 has functions independent of activating PD1 signaling. It is not known whether these cell-intrinsic functions of PD-L1 are shared among non-transformed and transformed cells, if they vary among cancer molecular subtypes, or if they are impacted by anti-PD-L1 therapy. Here we use quantitative microscopy techniques and APEX2 proximity mapping to describe the behavior of PD-L1 and to identify PD-L1's proximal proteome in human lung epithelial cells. Our data reveal growth factor control of PD-L1 recycling as a mechanism for acute and reversible regulation of PD-L1 density on the plasma membrane. In addition, we describe novel PD-L1 biology restricted to mutant EGFR cells. Anti-PD-L1 antibody treatment of mutant EGFR cells perturbs cell intrinsic PD-L1 functions, leading to reduced cell migration, increased half-life of EGFR and increased extracellular vesicle biogenesis, whereas anti-PD-L1 antibody does not induce these changes in wild type EGFR cells. Growth factor acute regulation of PD-L1 trafficking, by contributing to the control of plasma membrane density, might contribute to the regulation of PD-L1's immune checkpoint activity, whereas the specific effects of anti-PD-L1 on mutant EGFR cells might contribute to the poor anti-PD-L1 response of mutant EGFR tumors. Video Abstract The online version contains supplementary material available at 10.1186/s12964-023-01084-6.
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影响因子：
3.3
作者：
Hamanishi J;Mandai M;Matsumura N;Abiko K;Baba T;Konishi I
通讯作者：
Konishi I
影响因子：
14.8
作者：
Hung V;Udeshi ND;Lam SS;Loh KH;Cox KJ;Pedram K;Carr SA;Ting AY
通讯作者：
Ting AY
影响因子：
--
作者：
Arasanz H;Gato-Cañas M;Zuazo M;Ibañez-Vea M;Breckpot K;Kochan G;Escors D
通讯作者：
Escors D
影响因子：
64.5
作者：
Katzmann, DJ;Babst, M;Emr, SD
通讯作者：
Emr, SD
DOI：
10.1158/1541-7786.mcr-12-0437-t
发表时间：
2013-06
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Chaudhri VK;Salzler GG;Dick SA;Buckman MS;Sordella R;Karoly ED;Mohney R;Stiles BM;Elemento O;Altorki NK;McGraw TE
通讯作者：
McGraw TE