TY - JOUR
T1 - Heterogeneous Expression of PD-L1, B7x, B7-H3, and HHLA2 in Pulmonary Sarcomatoid Carcinoma and the Related Regulatory Signaling Pathways
AU - Wang, Feng
AU - Cali Daylan, Ayse Ece
AU - Deng, Lei
AU - Yang, Jihua
AU - Sharma, Janaki
AU - Su, Christopher
AU - Li, Shenduo
AU - Zang, Xingxing
AU - Halmos, Balazs
AU - Borczuk, Alain
AU - Cheng, Haiying
N1 - Publisher Copyright:
© 2023 by the authors.
PY - 2023/7
Y1 - 2023/7
N2 - 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%, p = 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, METex14 was detected in 19.5% of patients and was associated with a higher sarcomatoid percentage. Our preclinical studies revealed that METex14 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 METex14 in PSC and its role in regulating PD-L1 expression reveal different therapeutic targets in this aggressive NSCLC subtype.
AB - 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%, p = 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, METex14 was detected in 19.5% of patients and was associated with a higher sarcomatoid percentage. Our preclinical studies revealed that METex14 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 METex14 in PSC and its role in regulating PD-L1 expression reveal different therapeutic targets in this aggressive NSCLC subtype.
KW - METex14
KW - PD-L1
KW - immune checkpoint
KW - pulmonary sarcomatoid sarcoma
KW - signaling pathways
UR - http://www.scopus.com/inward/record.url?scp=85164702431&partnerID=8YFLogxK
U2 - 10.3390/cancers15133372
DO - 10.3390/cancers15133372
M3 - Article
C2 - 37444481
AN - SCOPUS:85164702431
SN - 2072-6694
VL - 15
JO - Cancers
JF - Cancers
IS - 13
M1 - 3372
ER -