Abstract
Immune checkpoint inhibitor (ICI) therapy has been established as one of the key treatment strategies for lung squamous cell carcinoma (LUSQ). The status of programmed death-ligand 1 (PD-L1) in tumor cells and/or immune cells using immunohistochemistry has been primarily used as a surrogate marker for determining ICI treatment; however, when the tissues to be examined are small, false-negative results could be unavoidable due to the heterogeneity of PD-L1 immunoreactivity. To overcome this practical limitation, we attempted to explore the status of nuclear atypia evaluated using morphometry as a potential predictor of PD-L1 status in LUSQ. We correlated the parameters related to nuclear atypia with PD-L1 status using two different cohorts of LUSQ patients (95 cases from The Cancer Genome Atlas database and 30 cases from the Miyagi Cancer Center). Furthermore, we studied the gene mutation status to elucidate the genetic profile of PD-L1 predictable cases. The results revealed that nuclear atypia, especially morphometric parameters related to nuclear shape irregularity, including aspect ratio, circularity, roundness, and solidity, were all significantly associated with PD-L1 status. Additionally, LUSQ cases with high PD-L1 expression and pronounced nuclear atypia were significantly associated with C10orf71 and COL14A1 mutations compared with those with low PD-L1 expression and mild nuclear atypia. We demonstrated for the first time that nuclear shape irregularity could represent a novel predictor of PD-L1 expression in LUSQ. Including the morphometric parameters related to nuclear atypia in conjunction with PD-L1 status could help determine an effective ICI therapeutic strategy; however, further investigation is required.
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Acknowledgements
We thank all the staff of the Department Pathology, Miyagi Cancer Center, for their technical support for the immunohistochemistry.
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This work was supported by the JSPS KAKENHI Grant Numbers JP20 K07387.
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All the authors have contributed significantly to the content of the manuscript. RS-K conceived and designed the study, and drafted the manuscript; KT, JY, and YO performed the gene mutation analysis and assisted the interpretation of the results; YY assisted the genetic experiments; CI and YM assisted the interpretation of the results; JA, HO, and IS participated in collection of clinical and histological data; JY and HS supervised all experiments and edited the manuscript. All the authors read and approved the final manuscript.
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The experiment reported here was conducted in agreement with the Declaration of Helsinki, and was approved by the Ethics Committee of Tohoku University (Miyagi, Japan) and that of Miyagi Cancer Center (Miyagi, Japan). Requirement of informed consent was waived.
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Saito-Koyama, R., Tamai, K., Yasuda, J. et al. Morphometric analysis of nuclear shape irregularity as a novel predictor of programmed death-ligand 1 expression in lung squamous cell carcinoma. Virchows Arch 484, 609–620 (2024). https://doi.org/10.1007/s00428-023-03548-z
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DOI: https://doi.org/10.1007/s00428-023-03548-z