Chemotherapy enhances programmed cell death 1/ligand 1 expression via TGF-β induced epithelial mesenchymal transition in non-small cell lung cancer
Open accessAbstract
In cancer immunology, the programmed cell death 1-programmed cell death 1/ligand 1 (PD-1/PD-L1) pathway plays a major role. Anti-PD-1 and anti-PD-L1 antibodies provide reliable immunotherapy when given as treatment for various types of malignancy including lung cancer. PD-L1 expression in cancer cells has been reported to be a predictive factor for the therapeutic effects of immunotherapy. However, the mechanism of PD-L1 expression remains unclear. Another key process in cancer progression is epithelial-mesenchymal transition (EMT). In the present study, we investigated the mechanism of PD-L1 expression as well as changes in its expression during the EMT process in non-small cell lung cancer (NSCLC). In this study, A549 cells underwent EMT by treatment with TGF-β or chemotherapeutic agents and then PD-L1 expression was evaluated. The alterations of PD-L1 expression was also examined during the reverse EMT process; mesenchymal-epithelial transition (MET). The relationship between for PD-L1 expression and EMT status in clinical specimens with NSCLC after induction chemotherapy were analyzed by immunohistochemical staining. We found that PD-L1 expression was upregulated following TGF-β induction; in contrast, it was downregulated by TGF-β receptor-kinase inhibitors and the MET process. Furthermore, chemo-treatment increased TGF-β expression and enhances PD-L1 expression via autocrine TGF-β induced EMT. Analysis of clinical samples revealed a significant relationship between PD-L1 expression and EMT status (P<0.05). In conclusion, our results suggest that PD-L1 expression is regulated by TGF-β induced EMT and enhanced by chemo-treatment via the chemo-induced TGF-β signaling. The anti-PD-1/PD-L1 blockade may provide more effective anticancer activities in combination with chemotherapy in NSCLC.
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TGF-β/Smad3 signaling enhances antigen-induced PD-1 expression on tumor-infiltrating T lymphocytes.
“TGF-β/Smad3 signaling enhances antigen-induced PD-1 expression on tumor infiltrating T lymphocytes364”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [364]
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Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer
Reck, M., Rodríguez-Abreu, D., Robinson, A. G., Hui, R., Csőszi, T., Fülöp, A., Gottfried, M., Peled, N., Tafreshi, A., Cuffe, S., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1606774 · Cited by 10,089 · see citing works
Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer
Borghaei, H., Paz-Ares, L., Horn, L., Spigel, D. R., Steins, M., Ready, N. E., Chow, L. Q., Vokes, E. E., Felip, E., Holgado, E., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1507643 · Cited by 9,335 · see citing works
Nivolumab versus Docetaxel in Advanced Squamous-Cell Non–Small-Cell Lung Cancer
Brahmer, J., Reckamp, K. L., Baas, P., Crinò, L., Eberhardt, W. E. E., Poddubskaya, E., Antonia, S., Pluzanski, A., Vokes, E. E., Holgado, E., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1504627 · Cited by 8,447 · see citing works
Iwai, Y., Ishida, M., Tanaka, Y., Okazaki, T., Honjo, T., & Minato, N. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.192461099 · Cited by 3,204 · see citing works
Weber, J. S., D’Angelo, S. P., Minor, D. R., Hodi, F. S., Gutzmer, R., Neyns, B., Höeller, C., Khushalani, N. I., Miller, W. H., Lao, C. D., et al. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(15)70076-8 · Cited by 2,676 · see citing works
Noman, M. Z., Desantis, G., Janji, B., Hasmim, M., Karray, S., Dessen, P., Bronte, V., & Chouaib, S. (2014) · Journal of Experimental Medicine · doi:10.1084/jem.20131916 · Cited by 2,166 · see citing works
Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice
Deng, L., Liang, H. L., Burnette, B., Beckett, M., Darga, T. E., Weichselbaum, R. R., & Fu, Y. (2014) · Journal of Clinical Investigation · doi:10.1172/jci67313 · Cited by 2,101 · see citing works
Acquired Resistance to Fractionated Radiotherapy Can Be Overcome by Concurrent PD-L1 Blockade
Dovedi, S. J., Adlard, A. L., Lipowska‐Bhalla, G., McKenna, C., Jones, S., Cheadle, E. J., Stratford, I. J., Poon, E., Morrow, M., Stewart, R. A., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-1258 · Cited by 1,316 · see citing works
McCarty, K. S., Szabo, E. M., Flowers, J. L., Cox, E. B., Leight, G. S., Miller, L. A., Konrath, J. G., Jt, S., Budwit, D. A., & Wt, C. (1986) · PubMed · Cited by 417 · see citing works
Shintani, Y., Fujiwara, A., Kimura, T., Kawamura, T., Funaki, S., Minami, M., & Okumura, M. (2016) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2016.05.025 · Cited by 294 · see citing works
Self-citationZhang, P., Su, D., Liang, M., & Fu, J. (2007) · Molecular Immunology · doi:10.1016/j.molimm.2007.08.013 · Cited by 262 · see citing works
Shintani, Y., Maeda, M., Chaika, N. V., Johnson, K. R., & Wheelock, M. J. (2007) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2007-0071oc · Cited by 259 · see citing works
Self-citationA systems view of epithelial–mesenchymal transition signaling states
Thomson, S., Petti, F., Sujka-Kwok, I., Mercado, P., Bean, J. M., Monaghan, M., Seymour, S. L., Argast, G. M., Epstein, D. M., & Haley, J. D. (2010) · Clinical & Experimental Metastasis · doi:10.1007/s10585-010-9367-3 · Cited by 210 · see citing works
Koh, J., Go, H., Keam, B., Kim, M., Nam, S. J., Kim, T. M., Lee, S., Min, H. S., Kim, Y. T., Kim, D., et al. (2015) · Modern Pathology · doi:10.1038/modpathol.2015.63 · Cited by 160 · see citing works
Shintani, Y., Okimura, A., Sato, K., Nakagiri, T., Kadota, Y., Inoue, M., Sawabata, N., Minami, M., Ikeda, N., Kawahara, K., et al. (2011) · The Annals of Thoracic Surgery · doi:10.1016/j.athoracsur.2011.07.032 · Cited by 159 · see citing works
Self-citationClinical and pathologic features of lung cancer expressing programmed cell death ligand 1 (PD-L1)
Shimoji, M., Shimizu, S., Sato, K., Suda, K., Kobayashi, Y., Tomizawa, K., Takemoto, T., & Mitsudomi, T. (2016) · Lung Cancer · doi:10.1016/j.lungcan.2016.04.021 · Cited by 157 · see citing works
Ock, C.-Y., Kim, S., Keam, B., Kim, M., Kim, T. M., Kim, J.-H., Jeon, Y. K., Lee, J., Kwon, S. K., Hah, J. H., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.7431 · Cited by 146 · see citing works
Hecht, M., Büttner-Herold, M. J., Erlenbach‐Wünsch, K., Haderlein, M., Croner, R. S., Grützmann, R., Hartmann, A., Fietkau, R., & Distel, L. V. (2016) · European Journal of Cancer · doi:10.1016/j.ejca.2016.06.015 · Cited by 127 · see citing works
Abulaiti, A., Shintani, Y., Funaki, S., Nakagiri, T., Inoue, M., Sawabata, N., Minami, M., & Okumura, M. (2013) · Lung Cancer · doi:10.1016/j.lungcan.2013.08.008 · Cited by 86 · see citing works
Self-citationQuantitative and qualitative characterization of Two PD-L1 clones: SP263 and E1L3N
Smith, J., Robida, M. D., Acosta, K., Vennapusa, B., Mistry, A., Martin, G. S., Yates, A., & Hnatyszyn, H. J. (2016) · Diagnostic Pathology · doi:10.1186/s13000-016-0494-2 · Cited by 71 · see citing works
Shintani, Y., Abulaiti, A., Kimura, T., Funaki, S., Nakagiri, T., Inoue, M., Sawabata, N., Minami, M., Morii, E., & Okumura, M. (2013) · The Annals of Thoracic Surgery · doi:10.1016/j.athoracsur.2013.03.092 · Cited by 57 · see citing works
Self-citationSchats, K., Vré, E. A. V., Schepper, S. D., Boeckx, C., Schrijvers, D. M., Waelput, W., Fransén, E., Bempt, I. V., Neyns, B., Meester, I. D., et al. (2016) · Histopathology · doi:10.1111/his.13056 · Cited by 38 · see citing works
Yang, Y., Pang, Z., Ding, N., Dong, W., Ma, W., Li, Y., Du, J., & Liu, Q. (2016) · Oncotarget · doi:10.18632/oncotarget.11291 · Cited by 36 · see citing works
Bordon, Y. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3880 · Cited by 25 · see citing works
Flagged first, then by citations
Cited by
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Derynck, R., Turley, S. J., & Akhurst, R. J. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-0403-1 · Cited by 944 · see citing works
van Staalduinen, J., Baker, D., ten Dijke, P., & van Dam, H. (2018) · Oncogene · doi:10.1038/s41388-018-0378-x · Cited by 158 · see citing works
Jung, A. R., Jung, C., Noh, J. K., Lee, Y. C., & Eun, Y. (2020) · Scientific Reports · doi:10.1038/s41598-020-60707-x · Cited by 97 · see citing works
MicroRNA regulation of liver cancer stem cells.
Lou, W., Liu, J., Gao, Y., Zhong, G., Ding, B., Xu, L., & Fan, W. (2018) · Europe PMC (PubMed Central) · Cited by 85 · see citing works
Programmed death ligand 1 immunohistochemistry in non-small cell lung carcinoma
Lantuéjoul, S., Damotte, D., Hofman, V., & Adam, J. (2019) · Journal of Thoracic Disease · doi:10.21037/jtd.2018.12.103 · Cited by 68 · see citing works
The Kraken Wakes: induced EMT as a driver of tumour aggression and poor outcome
Redfern, A. D., Spalding, L. J., & Thompson, E. W. (2018) · Clinical & Experimental Metastasis · doi:10.1007/s10585-018-9906-x · Cited by 64 · see citing works
Epithelial-to-Mesenchymal Transition in the Light of Plasticity and Hybrid E/M States
Bornes, L., Belthier, G., & van Rheenen, J. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10112403 · Cited by 59 · see citing works
Autocrine TGF-β in Cancer: Review of the Literature and Caveats in Experimental Analysis
Ungefroren, H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22020977 · Cited by 54 · see citing works
Finn, C. F., Spigel, D. R., Senan, S., Langer, C. J., Perez, B. A., Özgüroğlu, M., Daniel, D. B., Villegas, A. E., Vicente, D., Hui, R., et al. (2020) · Lung Cancer · doi:10.1016/j.lungcan.2020.11.024 · Cited by 50 · see citing works
Gaponova, A. V., Rodin, S., Mazina, A. A., & Volchkov, D. P. (2020) · Acta Naturae · doi:10.32607/actanaturae.11010 · Cited by 42 · see citing works
McCall, N. S., Dicker, A. P., & Lü, B. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-3269 · Cited by 41 · see citing works
Luo, X., Huang, W., Li, S., Sun, M., Hu, D. X., Jiang, J., Zhang, Z., Wang, Y., Wang, Y., Zhang, J., et al. (2024) · Advanced Science · doi:10.1002/advs.202310304 · Cited by 33 · see citing works
Shrestha, R., Bridle, K. R., Crawford, D. H., & Jayachandran, A. (2020) · Molecular Medicine Reports · doi:10.3892/mmr.2020.10991 · Cited by 34 · see citing works
The Role of Regulatory T Cells in Cancer Treatment Resistance
Dąbrowska, A., Grubba, M., Balihodzic, A., Szot, O., Sobocki, B. K., & Perdyan, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241814114 · Cited by 28 · see citing works
Lantuéjoul, S., Adam, J., Girard, N., Duruisseaux, M., Mansuet‐Lupo, A., Cazes, A., Rouquette, I., Gibault, L., Garcia, S., Antoine, M., et al. (2018) · Annales de Pathologie · doi:10.1016/j.annpat.2018.01.007 · Cited by 26 · see citing works
Cella, E., Zullo, L., Marconi, S., Rossi, G., Coco, S., Dellepiane, C., Alama, A., Rozeboom, L. M., Bennicelli, E., Parisi, F., et al. (2022) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2022.2116273 · Cited by 25 · see citing works
Funaki, S., Shintani, Y., Fukui, E., Yamamoto, Y., Kanzaki, R., Ose, N., Kanou, T., Minami, M., Mori, E., & Okumura, M. (2019) · Cancer Medicine · doi:10.1002/cam4.1943 · Cited by 26 · see citing works
Self-citationLiu, Z.-L., Liu, J., Staiculescu, D., & Chen, J. (2021) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359211018026 · Cited by 24 · see citing works
Strait, A. A., Woolaver, R. A., Hall, S. C., Young, C. D., Karam, S. D., Jimeno, A., Lan, Y., Raben, D., Wang, J. H., & Wang, J. H. (2021) · Communications Biology · doi:10.1038/s42003-021-02522-2 · Cited by 22 · see citing works
Immune checkpoints between epithelial-mesenchymal transition and autophagy: A conflicting triangle
Cordani, M., Strippoli, R., Trionfetti, F., Behrooz, A. B., Rumio, C., Velasco, G., Ghavami, S., & Marcucci, F. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.216661 · Cited by 20 · see citing works
Ancel, J., Dewolf, M., Deslée, G., Nawrocki‐Raby, B., Dalstein, V., Gilles, C., & Polette, M. (2020) · Cells Tissues Organs · doi:10.1159/000510103 · Cited by 19 · see citing works
The effects of chemotherapeutic drugs on PD-L1 gene expression in breast cancer cell lines
Majidi, M., Safaee, S., Amini, M. A., Baghbanzadeh, A., Hajiasgharzadeh, K., Hashemzadeh, S., Shotorbani, S. S., Mokhtarzadeh, A., & Baradaran, B. (2021) · Medical Oncology · doi:10.1007/s12032-021-01556-0 · Cited by 19 · see citing works
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Melillo, G., Chand, V. K., Yovine, A. J., Gupta, A. K., & Massacesi, C. (2021) · Advances in Therapy · doi:10.1007/s12325-021-01675-0 · Cited by 16 · see citing works
Li, Z., Wang, F., Dang, J., Cheng, F., & Zheng, F. (2022) · Translational Cancer Research · doi:10.21037/tcr-22-292 · Cited by 14 · see citing works
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Lingling, Z., Liu, J., Li, W., Danli, Y., Jie, Z., Li, W., Pu, D., Lei, P., & Qinghua, Z. (2020) · Pathology - Research and Practice · doi:10.1016/j.prp.2020.152852 · Cited by 15 · see citing works
Zhou, Y., Wang, F., Li, G., Xu, J., Zhang, J., Gullen, E. A., Yang, J., & Wang, J. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1340307 · Cited by 13 · see citing works
Wang, Y., Yang, B., Zhao, J., Yu, X., Liu, X., Zhang, L., Zhang, Y., Li, X., & Zhai, Z. (2019) · Molecular Medicine Reports · doi:10.3892/mmr.2019.9814 · Cited by 13 · see citing works
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Hu, S., Yan, C., Tian, Y., & Sun, W. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-07084-z · Cited by 11 · see citing works
Xiao, F., Liu, Y., Zhang, Z., Wang, L., Wang, T., & Wang, X. (2020) · Thoracic Cancer · doi:10.1111/1759-7714.13533 · Cited by 6 · see citing works
Zhou, S., Zhang, Q., Han, H., Chen, G., Wang, P., Xue, S., Pei, Q., Xie, Z., & Meng, X. (2025) · Journal of Nanobiotechnology · doi:10.1186/s12951-025-03894-x · Cited by 4 · see citing works
Funaki, S., Ose, N., Kimura, T., Kanou, T., Fukui, E., & Shintani, Y. (2022) · Thoracic Cancer · doi:10.1111/1759-7714.14681 · Cited by 4 · see citing works
Self-citationHirose, K., Otsu, H., Masuda, T., Saeki, H., Tobo, T., Hosoda, K., Matsumoto, C., Tatsumi, T., Ikehara, T., Ofuchi, T., et al. (2025) · Annals of Surgical Oncology · doi:10.1245/s10434-025-17710-1 · Cited by 4 · see citing works
Serrán, M. G., Vernengo, F. F., Almada, L., Beccaría, C. G., Gazzoni, Y., Cañete, P. F., Roco, J. A., Tosello, J., Ramello, M. C., Wehrens, E. J., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.828734 · Cited by 4 · see citing works
Alabi, F. A., Okpalanwaka, I. F., Oyegbesan, A., Okoyeocha, E. O. M., Oladejo, M., & Imodoye, S. O. (2025) · MedComm – Oncology · doi:10.1002/mog2.70027 · Cited by 3 · see citing works
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Frelau, A., Pracht, M., Sourd, S. L., Lespagnol, A., Corre, R., Menard, C., Tarte, K., Mosser, J., & Edeline, J. (2018) · Bulletin du Cancer · doi:10.1016/s0007-4551(18)30393-x · Cited by 3 · see citing works
Morais, H. G. D. F., Martins, H. D. D., da Paz, A. R., de Morais, É. F., Bonan, P. R. F., & Freitas, R. D. A. (2025) · Archives of Oral Biology · doi:10.1016/j.archoralbio.2025.106304 · Cited by 2 · see citing works
Garassino, M. C., Paz-Ares, L. G., Hui, R., Finn, C. F., Spira, A. I., Planchard, D., Özgüroğlu, M., Daniel, D. B., Vicente, D., Murakami, S., et al. (2021) · Future Oncology · doi:10.2217/fon-2020-1102 · Cited by 2 · see citing works
Nakazono, C., Okada, S., Tando, S., Ishihara, S., Shimomura, M., Furuya, T., Kameyama, K., Küffer, S., Müller, D., Marx, A., et al. (2025) · Cancer Science · doi:10.1111/cas.70243 · Cited by 1 · see citing works
Figueiredo, M. I., de Sousa, V. M. L., & Carvalho, L. (2021) · Research Square · doi:10.21203/rs.3.rs-1135697/v1 · Cited by 1 · see citing works
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Frelau, A., Pracht, M., Sourd, S. L., Lespagnol, A., Corre, R., Menard, C., Tarte, K., Mosser, J., & Edeline, J. (2018) · Bulletin du Cancer · doi:10.1016/j.bulcan.2017.10.031
Molecular signalling and interactions in colon cancer stem cells
Chruścik, A. (2019) · Griffith Research Online · doi:10.25904/1912/3787
Kim, S.-Y., Park, D., Sun, P., Kim, N., Lee, D., Kim, D. K., Lee, S., Lee, J. E., Chung, C., & Kang, D. H. (2024) · Translational Lung Cancer Research · doi:10.21037/tlcr-24-392
- Authors
- Funaki, S., Shintani, Y., Kawamura, T., Kanzaki, R., Minami, M., & Okumura, M.
- Affiliations
- The University of Osaka (JP)
- ORCID
- Venue
- Oncology Reports
- Publisher
- Spandidos Publications
- Published
- 2017-04
- Volume
- 38
- Issue
- 4
- Pages
- 2277-2284
- ISSN
- 1021-335X (ISSN-L)
- 1791-2431
- OpenAlex
- W2744780444
- Cited by
- 43
- References
- 24
- Citations by year
- 2025: 6 · 2024: 5 · 2023: 1 · 2022: 4 · 2021: 8 · 2020: 8 · 2019: 4 · 2018: 7
- FWCI
- 2.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Oncology Reports (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (16K10680)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- PD-L1 expression, PD-1/PD-L1 pathway, epithelial-mesenchymal transition, mesenchymal-epithelial transition, TGF-beta signaling, non-small cell lung cancer, PD-1/PD-L1 blockade, A549 cells
- MeSH terms
- A549 Cells, Receptor, Transforming Growth Factor-beta Type II, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Female, Humans, Male, Middle Aged, Signal Transduction, Gene Expression Regulation, Neoplastic, Transforming Growth Factor beta, Protein Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Protein Kinase Inhibitors, Epithelial-Mesenchymal Transition, B7-H1 Antigen, Programmed Cell Death 1 Receptor
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