Wang Feng, Cali Daylan Ayse Ece, Deng Lei, Yang Jihua, Sharma Janaki, Su Christopher, Li Shenduo, Zang Xingxing, Halmos Balazs, Borczuk Alain, Cheng Haiying
Department of Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Department of Oncology, Montefiore Medical Center, Bronx, NY 10467, USA.
Cancers (Basel). 2023 Jun 27;15(13):3372. doi: 10.3390/cancers15133372.
Immunotherapy has transformed lung cancer management, but PSC remains an aggressive subtype with a poor prognosis. This study investigates the differential expression of PD-L1 and alternative immune checkpoints (ICs; B7x, B7-H3, and HHLA2), and genetic alterations in PSCs. Tumor specimens of 41 PSC patients were evaluated. PD-L1, B7x, B7-H3, and HHLA2 were positive in 75.0%, 67.6%, 73.0%, and 91.9% of tumors, respectively. PD-L1 expression was significantly higher in the epithelial compared to the sarcomatoid component (median TPS: 50% vs. 0%, = 0.010). Expression of PD-L1 in both components was only seen in 32.1% of patients. However, at least one IC was expressed in 92.9% of epithelial and 100% of sarcomatoid components. Furthermore, ex14 was detected in 19.5% of patients and was associated with a higher sarcomatoid percentage. Our preclinical studies revealed that ex14 induced PD-L1 expression via MAPK or PI3K/Akt pathways, and MET inhibitors decreased PD-L1 expression. Our findings demonstrate distinct expressions of ICs in PSC subcomponents. Thus, combination IC inhibition as a therapeutic strategy in PSC warrants further exploration. A high percentage of ex14 in PSC and its role in regulating PD-L1 expression reveal different therapeutic targets in this aggressive NSCLC subtype.
免疫疗法已经改变了肺癌的治疗方式，但肺肉瘤样癌（PSC）仍然是一种侵袭性亚型，预后较差。本研究调查了程序性死亡受体配体1（PD-L1）和其他免疫检查点（ICs；B7x、B7-H3和HHLA2）的差异表达，以及PSC中的基因改变。对41例PSC患者的肿瘤标本进行了评估。PD-L1、B7x、B7-H3和HHLA2在肿瘤中的阳性率分别为75.0%、67.6%、73.0%和91.9%。与肉瘤样成分相比，上皮成分中PD-L1表达显著更高（中位肿瘤比例评分：50%对0%，P = 0.010）。仅32.1%的患者在两种成分中均有PD-L1表达。然而，至少一种IC在92.9%的上皮成分和100%的肉瘤样成分中表达。此外，19.5%的患者检测到第14外显子（ex14）缺失，且与更高的肉瘤样比例相关。我们的临床前研究表明，ex14通过丝裂原活化蛋白激酶（MAPK）或磷脂酰肌醇-3-激酶/蛋白激酶B（PI3K/Akt）途径诱导PD-L1表达，而MET抑制剂可降低PD-L1表达。我们的研究结果表明ICs在PSC亚成分中有不同表达。因此，联合IC抑制作为PSC的一种治疗策略值得进一步探索。PSC中高比例的ex14及其在调节PD-L1表达中的作用揭示了这种侵袭性非小细胞肺癌（NSCLC）亚型的不同治疗靶点。
