Heterogeneous Expression of PD-L1, B7x, B7-H3, and HHLA2 in Pulmonary Sarcomatoid Carcinoma and the Related Regulatory Signaling Pathways
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...
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MDPI AG
2023-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/13/3372 |
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| author | Feng Wang Ayse Ece Cali Daylan Lei Deng Jihua Yang Janaki Sharma Christopher Su Shenduo Li Xingxing Zang Balazs Halmos Alain Borczuk Haiying Cheng |
| author_facet | Feng Wang Ayse Ece Cali Daylan Lei Deng Jihua Yang Janaki Sharma Christopher Su Shenduo Li Xingxing Zang Balazs Halmos Alain Borczuk Haiying Cheng |
| author_sort | Feng Wang |
| collection | DOAJ |
| description | 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%, <i>p</i> = 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, <i>MET</i>ex14 was detected in 19.5% of patients and was associated with a higher sarcomatoid percentage. Our preclinical studies revealed that <i>MET</i>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 <i>MET</i>ex14 in PSC and its role in regulating PD-L1 expression reveal different therapeutic targets in this aggressive NSCLC subtype. |
| first_indexed | 2024-03-11T01:46:23Z |
| format | Article |
| id | doaj.art-aca5c64cc23c416ab8f7a20ed50fd47b |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T01:46:23Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-aca5c64cc23c416ab8f7a20ed50fd47b2023-11-18T16:16:03ZengMDPI AGCancers2072-66942023-06-011513337210.3390/cancers15133372Heterogeneous Expression of PD-L1, B7x, B7-H3, and HHLA2 in Pulmonary Sarcomatoid Carcinoma and the Related Regulatory Signaling PathwaysFeng Wang0Ayse Ece Cali Daylan1Lei Deng2Jihua Yang3Janaki Sharma4Christopher Su5Shenduo Li6Xingxing Zang7Balazs Halmos8Alain Borczuk9Haiying Cheng10Department of Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USADepartment of Oncology, Montefiore Medical Center, Bronx, NY 10467, USADepartment of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USADepartment of Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USADepartment of Medicine, University of Miami Health System, Miami, FL 33136, USADepartment of Medicine, University of Washington, Seattle, WA 98195, USADepartment of Medicine, Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL 32224, USADepartment of Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USADepartment of Oncology, Montefiore Medical Center, Bronx, NY 10467, USADepartment of Pathology, Weill Cornell Medicine, New York, NY 10065, USADepartment of Oncology, Montefiore Medical Center, Bronx, NY 10467, USAImmunotherapy 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%, <i>p</i> = 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, <i>MET</i>ex14 was detected in 19.5% of patients and was associated with a higher sarcomatoid percentage. Our preclinical studies revealed that <i>MET</i>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 <i>MET</i>ex14 in PSC and its role in regulating PD-L1 expression reveal different therapeutic targets in this aggressive NSCLC subtype.https://www.mdpi.com/2072-6694/15/13/3372immune checkpointpulmonary sarcomatoid sarcoma<i>MET</i>ex14PD-L1signaling pathways |
| spellingShingle | Feng Wang Ayse Ece Cali Daylan Lei Deng Jihua Yang Janaki Sharma Christopher Su Shenduo Li Xingxing Zang Balazs Halmos Alain Borczuk Haiying Cheng Heterogeneous Expression of PD-L1, B7x, B7-H3, and HHLA2 in Pulmonary Sarcomatoid Carcinoma and the Related Regulatory Signaling Pathways Cancers immune checkpoint pulmonary sarcomatoid sarcoma <i>MET</i>ex14 PD-L1 signaling pathways |
| title | Heterogeneous Expression of PD-L1, B7x, B7-H3, and HHLA2 in Pulmonary Sarcomatoid Carcinoma and the Related Regulatory Signaling Pathways |
| title_full | Heterogeneous Expression of PD-L1, B7x, B7-H3, and HHLA2 in Pulmonary Sarcomatoid Carcinoma and the Related Regulatory Signaling Pathways |
| title_fullStr | Heterogeneous Expression of PD-L1, B7x, B7-H3, and HHLA2 in Pulmonary Sarcomatoid Carcinoma and the Related Regulatory Signaling Pathways |
| title_full_unstemmed | Heterogeneous Expression of PD-L1, B7x, B7-H3, and HHLA2 in Pulmonary Sarcomatoid Carcinoma and the Related Regulatory Signaling Pathways |
| title_short | Heterogeneous Expression of PD-L1, B7x, B7-H3, and HHLA2 in Pulmonary Sarcomatoid Carcinoma and the Related Regulatory Signaling Pathways |
| title_sort | heterogeneous expression of pd l1 b7x b7 h3 and hhla2 in pulmonary sarcomatoid carcinoma and the related regulatory signaling pathways |
| topic | immune checkpoint pulmonary sarcomatoid sarcoma <i>MET</i>ex14 PD-L1 signaling pathways |
| url | https://www.mdpi.com/2072-6694/15/13/3372 |
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