Cancer Research and Treatment

Original Articles

Genitourinary cancer

PD-L1 Upregulation by the mTOR Pathway in VEGFR-TKI–Resistant Metastatic Clear Cell Renal Cell Carcinoma: Se Un Jeong, Hee Sang Hwang, Ja-Min Park, Sun Young Yoon, Su-Jin Shin, Heounjeong Go, Jae-Lyun Lee, Gowun Jeong, Yong Mee Cho; Cancer Res Treat. 2023;55(1):231-244. Published online March 2, 2022; DOI: https://doi.org/10.4143/crt.2021.1526

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Purpose
Tyrosine kinase inhibitors (TKI) targeting vascular endothelial growth factor receptor (VEGFR) signaling pathways have been used for metastatic clear cell renal cell carcinoma (mCCRCC), but resistance to the drug develops in most patients. We aimed to explore the underlying mechanism of the TKI resistance with regard to programmed death-ligand 1 (PD-L1) and to investigate signaling pathway associated with the resistant mechanism.
Materials and Methods
To determine the mechanism of resistance, 10 mCCRCC patients from whom tumor tissues were harvested at both the pretreatment and the TKI-resistant post-treatment period were included as the discovery cohort, and their global gene expression profiles were compared. A TKI-resistant renal cancer cell line was established by long-term treatment with sunitinib.
Results
Among differentially expressed genes in the discovery cohort, increased PD-L1 expression in post-treatment tissues was noted in four patients. Pathway analysis showed that PD-L1 expression was positively correlated with the mammalian target of rapamycin (mTOR) signaling pathway. The TKI-resistant renal cancer cells showed increased expression of PD-L1 and mTOR signaling proteins and demonstrated aggressive tumoral behaviour. Treatment with mTOR inhibitors down-regulated PD-L1 expression and suppressed aggressive tumoral behaviour, which was reversed with stimulation of the mTOR pathway.
Conclusion
These results showed that PD-L1 expression may be increased in a subset of VEGFR-TKI–resistant mCCRCC patients via the mTOR pathway.

Citations

Citations to this article as recorded by

IFITM3-mediated activation of TRAF6/MAPK/AP-1 pathways induces acquired TKI resistance in clear cell renal cell carcinoma
Se Un Jeong, Ja-Min Park, Sun Young Yoon, Hee Sang Hwang, Heounjeong Go, Dong-Myung Shin, Hyein Ju, Chang Ohk Sung, Jae-Lyun Lee, Gowun Jeong, Yong Mee Cho
Investigative and Clinical Urology.2024; 65(1): 84. CrossRef
Targeting apoptosis in clear cell renal cell carcinoma
Adam Kowalewski, Jędrzej Borowczak, Mateusz Maniewski, Karol Gostomczyk, Dariusz Grzanka, Łukasz Szylberg
Biomedicine & Pharmacotherapy.2024; 175: 116805. CrossRef
Therapeutic advances of targeting receptor tyrosine kinases in cancer
Ciprian Tomuleasa, Adrian-Bogdan Tigu, Raluca Munteanu, Cristian-Silviu Moldovan, David Kegyes, Anca Onaciu, Diana Gulei, Gabriel Ghiaur, Hermann Einsele, Carlo M. Croce
Signal Transduction and Targeted Therapy.2024;[Epub] CrossRef
Mechanisms of sunitinib resistance in renal cell carcinoma and associated opportunities for therapeutics
Yunxia Wang, Xiaolin Liu, Luyao Gong, Weihong Ding, Wenjing Hao, Yeheng Peng, Jun Zhang, Weimin Cai, Yuan Gao
British Journal of Pharmacology.2023; 180(23): 2937. CrossRef
Prior Anti-Angiogenic TKI-Based Treatment as Potential Predisposing Factor to Nivolumab-Mediated Recurrent Thyroid Disorder Adverse Events in mRCC Patients: A Case Series
Luigi Liguori, Angelo Luciano, Giovanna Polcaro, Alessandro Ottaiano, Marco Cascella, Francesco Perri, Stefano Pepe, Francesco Sabbatino
Biomedicines.2023; 11(11): 2974. CrossRef

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Gastrointestinal cancer

Prognostic Value of Serum Soluble Programmed Death-Ligand 1 and Dynamics During Chemotherapy in Advanced Gastric Cancer Patients: Woochan Park, Ju-Hee Bang, Ah-Rong Nam, Mei Hua Jin, Hyerim Seo, Jae-Min Kim, Kyoung Seok Oh, Tae-Yong Kim, Do-Youn Oh; Cancer Res Treat. 2021;53(1):199-206. Published online October 6, 2020; DOI: https://doi.org/10.4143/crt.2020.497

Abstract PDF Supplementary Material PubReader ePub

Purpose
The soluble form programmed death-ligand 1 (sPDL1) has immunosuppressive properties and is being studied as a candidate biomarker for immuno-oncology drug development. We measured the serum sPDL1 at pre-and post-chemotherapy and evaluated its prognostic implication and dynamics during chemotherapy in advanced gastric cancer (GC).
Materials and Methods
We prospectively enrolled 68 GC patients who were candidates for palliative standard first-line chemotherapy, and serially collected blood at baseline and after one cycle of chemotherapy, at the best response and after disease progression. sPDL1 was measured using an enzyme-linked immunosorbent assay. Response to chemotherapy, overall survival (OS), progressionfree survival (PFS) and other prognostic factors including neutrophil-lymphocyte ratio (NLR) were obtained. The cut-off value of sPDL1 levels for survival analysis was found using C-statistics.
Results
The median baseline sPDL1 was 0.8 ng/mL (range, 0.06 to 6.06 ng/mL). The median OS and PFS were 14.9 months and 8.0 months, respectively. sPDL1 and NLR showed a weak positive correlation (Spearman’s rho=0.301, p=0.013). Patients with low levels of sPDL1 at diagnosis (< 1.92 ng/mL) showed a better OS and PFS than patients with a high sPDL1. The baseline sPDL1 before treatment was higher in the progressive disease group than in the stable disease and partial response groups. Patients whose sPDL1 increased after the first cycle of chemotherapy showed worse PFS and OS. Following disease progression, sPDL1 increased compared with the baseline.
Conclusion
sPDL1 at prechemotherapy confers a prognostic value for PFS and OS in GC patients under palliative first-line chemotherapy. Dynamics of sPDL1 during chemotherapy correlates with disease progression.

Citations

Citations to this article as recorded by

Laccase-inspired bi-amino acid MOFs with high substrate affinity: Catalytic deposition induced “signal-down” electrochemical response towards PD-L1
Ruhui Hu, Suyun Zhong, Hezhen Liu, Yawen Liu, Hongxia Chen, Xiaojun Hu
Sensors and Actuators B: Chemical.2024; 399: 134773. CrossRef
Prognostic significance of soluble PD-L1 in prostate cancer
Margarita Zvirble, Zilvinas Survila, Paulius Bosas, Neringa Dobrovolskiene, Agata Mlynska, Gintaras Zaleskis, Jurgita Jursenaite, Dainius Characiejus, Vita Pasukoniene
Frontiers in Immunology.2024;[Epub] CrossRef
CRP and soluble CTLA4 are determinants of anti-PD1 resistance in gastrointestinal cancer
Kotoe Oshima
American Journal of Cancer Research.2024; 14(3): 1174. CrossRef
Soluble immune checkpoint molecules in cancer risk, outcomes prediction, and therapeutic applications
Lin Chen, Yuqing Chao, Wenjing Li, Zhixia Wu, Qinchuan Wang
Biomarker Research.2024;[Epub] CrossRef
Myeloid subsets impede the efficacy of anti-PD1 therapy in patients with advanced gastric cancer (WJOG10417GTR study)
Hirokazu Shoji, Chie Kudo-Saito, Kengo Nagashima, Hiroshi Imazeki, Kai Tsugaru, Naoki Takahashi, Takeshi Kawakami, Yusuke Amanuma, Takeru Wakatsuki, Naohiro Okano, Yukiya Narita, Yoshiyuki Yamamoto, Rika Kizawa, Kei Muro, Kazunori Aoki, Narikazu Boku
Journal for ImmunoTherapy of Cancer.2024; 12(11): e010174. CrossRef
Prognostic value of tumor mutation burden in patients with advanced gastric cancer receiving first-line chemotherapy
Xiao-Peng Duan, Ke Liu, Xiao-Dong Jiao, Bao-Dong Qin, Bing Li, Xi He, Yan Ling, Ying Wu, Shi-Qi Chen, Yuan-Sheng Zang
Frontiers in Oncology.2023;[Epub] CrossRef
Prognostic value of soluble PD-L1 and exosomal PD-L1 in advanced gastric cancer patients receiving systemic chemotherapy
Kabsoo Shin, Joori Kim, Se Jun Park, Myung Ah Lee, Jae Myung Park, Myung-Gyu Choi, Donghoon Kang, Kyo Young Song, Han Hong Lee, Ho Seok Seo, Sung Hak Lee, Bohyun Kim, Okran Kim, Juyeon Park, Nahyeon Kang, In-Ho Kim
Scientific Reports.2023;[Epub] CrossRef
Site-specific protein biomarkers in gastric cancer: a comprehensive review of novel biomarkers and clinical applications
Takahiro Shinozuka, Mitsuro Kanda, Yasuhiro Kodera
Expert Review of Molecular Diagnostics.2023; 23(8): 701. CrossRef
The predictive role of soluble programmed death ligand 1 in digestive system cancers
Jian Ruan, Zhihong Zhao, Yuting Qian, Ruilian Xu, Guixiang Liao, Feng-Ming (Spring) Kong
Frontiers in Oncology.2023;[Epub] CrossRef
Does Elevated Pre-Treatment Plasma PD-L1 Level Indicate an Increased Tumor Burden and Worse Prognosis in Metastatic Colorectal Cancer?
Magdolna Dank, Dorottya Mühl, Magdolna Herold, Lilla Hornyák, Attila Marcell Szasz, Zoltan Herold
Journal of Clinical Medicine.2022; 11(16): 4815. CrossRef
How to Best Exploit Immunotherapeutics in Advanced Gastric Cancer: Between Biomarkers and Novel Cell-Based Approaches
Michele Ghidini, Angelica Petrillo, Andrea Botticelli, Dario Trapani, Alessandro Parisi, Anna La Salvia, Elham Sajjadi, Roberto Piciotti, Nicola Fusco, Shelize Khakoo
Journal of Clinical Medicine.2021; 10(7): 1412. CrossRef

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Alterations in PD-L1 Expression Associated with Acquisition of Resistance to ALK Inhibitors in ALK-Rearranged Lung Cancer: Su-Jung Kim, Soyeon Kim, Dong-Wan Kim, Miso Kim, Bhumsuk Keam, Tae Min Kim, Yusoo Lee, Jaemoon Koh, Yoon Kyung Jeon, Dae Seog Heo; Cancer Res Treat. 2019;51(3):1231-1240. Published online December 31, 2018; DOI: https://doi.org/10.4143/crt.2018.486

Abstract PDF Supplementary Material PubReader ePub

Purpose
The purpose of this study was to evaluate the relationships between the resistance of anaplastic lymphoma kinase (ALK)‒positive non-small cell lung cancer (NSCLC) to ALK inhibitors and the programmed cell death-1/programmed cell death–ligand 1 (PD-L1) pathway, we evaluated alterations in PD-L1 following acquisition of resistance to ALK inhibitors in ALK-positive lung cancer.
Materials and Methods
We established ALK inhibitor-resistant cell lines (H3122CR1, LR1, and CH1) by exposing the parental H3122 ALK-translocated NSCLC cell line to ALK inhibitors. Then, the double-resistant cell lines H3122CR1LR1 and CR1CH1 were developed by exposing the H3122CR1 to other ALK inhibitors. We compared the alterations in PD-L1 expression levels using western blotting, flow cytometry, and quantitative polymerase chain reaction. We also investigated gene expression using RNA sequencing. The expression of PD-L1 in the tumors from 26 ALK-positive metastatic NSCLC patients (11 ALK inhibitor-naïve and 15 ALK inhibitor-resistant patients) was assessed by immunohistochemistry and analyzed.
Results
PD-L1 was expressed at higher levels in ALK inhibitor-resistant cell lines than in the ALK inhibitor-naïve parental cell line at the total protein, surface protein, and mRNA levels. Furthermore, PD-L1 expression in the double-resistant cell lines was much higher than that in the single resistant cell lines. RNA sequencing demonstrated that expression of immune-related genes were largely involved in ALK inhibitor resistance. The mean value of the PD-L1 H-score was 6.5 pre-treatment and 35.0 post-treatment, and the fold difference was 5.42 (p=0.163).
Conclusion
PD-L1 expression increased following acquisition of ALK inhibitor resistance in ALK-positive NSCLC cell lines and tumors.

Citations

Citations to this article as recorded by

Association of PD-L1 expression and clinical outcomes in ROS1 - rearranged advanced non-small cell lung cancer treated with crizotinib
Huixian Zhang, Ziheng Zhang, Ningning Yan, Xingya Li
Frontiers in Oncology.2024;[Epub] CrossRef
Co-Occurrence of ALK rearrangement and KRAS G12C mutation in NSCLC: Report of two cases
M Siringo, F Larocca, A Spagnuolo, G Gentile, M Anile, D Diso, D Santini, A Gelibter
Current Problems in Cancer: Case Reports.2024; 14: 100291. CrossRef
Characterizing the immune tumor microenvironment in ALK fusion-positive lung cancer: state-of-the-art and therapeutical implications
Marco Sposito, Serena Eccher, Luca Pasqualin, Ilaria Mariangela Scaglione, Alice Avancini, Daniela Tregnago, Ilaria Trestini, Jessica Insolda, Adele Bonato, Stefano Ugel, Lisa Derosa, Michele Milella, Sara Pilotto, Lorenzo Belluomini
Expert Review of Clinical Immunology.2024; 20(8): 959. CrossRef
Comparing Genomic Profiles of ALK Fusion-Positive and ALK Fusion-Negative Nonsmall Cell Lung Cancer Patients
Wenchao Xia, Jing Yang, Hongbin Li, Ling Li, Jinfeng Liu
Global Medical Genetics.2024; 11(02): 175. CrossRef
Changes of tumor microenvironment in non-small cell lung cancer after TKI treatments
Shanshan Chen, Jingyi Tang, Fen Liu, Wei Li, Ting Yan, Dangang Shangguan, Nong Yang, Dehua Liao
Frontiers in Immunology.2023;[Epub] CrossRef
High PD-L1 Expression Correlates with an Immunosuppressive Tumour Immune Microenvironment and Worse Prognosis in ALK-Rearranged Non-Small Cell Lung Cancer
Xia Tian, Yalun Li, Qin Huang, Hao Zeng, Qi Wei, Panwen Tian
Biomolecules.2023; 13(6): 991. CrossRef
Spoilt for choice: different immunosuppressive potential of anaplastic lymphoma kinase inhibitors for non small cell lung cancer
Annkristin Heine, Stefanie Andrea Erika Held, Solveig Nora Daecke, Chrystel Flores, Peter Brossart
Frontiers in Immunology.2023;[Epub] CrossRef
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Ye Guo, Hanfei Guo, Yongfei Zhang, Jiuwei Cui
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Current Oncology.2022; 30(1): 518. CrossRef
The role of immunotherapy in fusion-driven lung cancer
Aaron C. Tan, Johan Chan, Mustafa Khasraw
Expert Review of Anticancer Therapy.2021; 21(5): 461. CrossRef
ARIH1 signaling promotes anti-tumor immunity by targeting PD-L1 for proteasomal degradation
Youqian Wu, Chao Zhang, Xiaolan Liu, Zhengfu He, Bing Shan, Qingxin Zeng, Qingwei Zhao, Huaying Zhu, Hongwei Liao, Xufeng Cen, Xiaoyan Xu, Mengmeng Zhang, Tingjun Hou, Zhe Wang, Huanhuan Yan, Shuying Yang, Yaqin Sun, Yanying Chen, Ronghai Wu, Tingxue Xie,
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Pan-cancer Analysis of Tumor Mutational Burden and Homologous Recombination DNA Damage Repair Using Targeted Next-Generation Sequencing
Hai-Yun Wang, Ling Deng, Ying-Qing Li, Xiao Zhang, Ya-Kang Long, Xu Zhang, Yan-Fen Feng, Yuan He, Tao Tang, Xin-Hua Yang, Fang Wang
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Sara Cavallaro, Petra Hååg, Siddharth S. Sahu, Lorenca Berisha, Vitaliy O. Kaminskyy, Simon Ekman, Rolf Lewensohn, Jan Linnros, Kristina Viktorsson, Apurba Dev
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