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J. Immunother. Cancer, Mar 06 2025, 13 (3) e010612 | https://doi.org/10.1136/jitc-2024-010612
Cell-intrinsic PD-L1 signaling drives immunosuppression by myeloid-derived suppressor cells through IL-6/Jak/Stat3 in PD-L1-high lung cancer
Hyein Jeong1,2, Jaemoon Koh3, Sehui Kim4, Jeemin Yim3,5, Seung Geun Song3,6,7, Hanbyeol Kim1,6,7,8, Yingying Li1,6,7,8, Soo Hyun Lee1,6,7,8, Yeon Kyu Chung9, Hongsoon Kim1,2, Chul-Hwan Lee1,6,7,8, Hye Young Kim6,7,10, Bhumsuk Keam1,11, Se-Hoon Lee12,13, Doo Hyun Chung3,6,7 and Yoon Kyung Jeon1,2,3,14
1Cancer Research Institute, Seoul National University, Seoul, Korea (the Republic of)
2Interdiscipilinary Program of Cancer Biology, Seoul National University Graduate School, Seoul, Korea (the Republic of)
3Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
4Department of Pathology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea (the Republic of)
5Department of Pathology, Boramae Medical Center, Seoul National University, Seoul, Korea (the Republic of)
6Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
7BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
8Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
9Seoul National University College of Medicine, Seoul, Korea (the Republic of)
10Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea (the Republic of)
11Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
12Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Gangnam-gu, Korea (the Republic of)
13Department of Health Sciences and Technology, Samsung Advanced Institute of Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea (the Republic of)
14BK21 FOUR Smart Healthcare, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
Correspondence to Dr Yoon Kyung Jeon
1Cancer Research Institute, Seoul National University, Seoul, Korea (the Republic of)
2Interdiscipilinary Program of Cancer Biology, Seoul National University Graduate School, Seoul, Korea (the Republic of)
3Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
4Department of Pathology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea (the Republic of)
5Department of Pathology, Boramae Medical Center, Seoul National University, Seoul, Korea (the Republic of)
6Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
7BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
8Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
9Seoul National University College of Medicine, Seoul, Korea (the Republic of)
10Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea (the Republic of)
11Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
12Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Gangnam-gu, Korea (the Republic of)
13Department of Health Sciences and Technology, Samsung Advanced Institute of Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea (the Republic of)
14BK21 FOUR Smart Healthcare, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
Correspondence to Dr Yoon Kyung Jeon
Abstract
Background Some patients with non-small-cell lung cancer (NSCLC) benefit from immune checkpoint inhibitors (ICIs) despite programmed death-ligand 1 (PD-L1) expression. To address the mechanism of ICI resistance in PD-L1-positive NSCLC, we investigated the role of tumor-cell-intrinsic function of PD-L1 in interleukin (IL)-6-mediated immunosuppression.
Methods Cohorts of NSCLC patients treated with ICI and public datasets were analyzed. PD-L1-overexpressing and PD-L1-knockdown NSCLC cells were submitted to RNA-seq, in vitro analyses, chromatin immunoprecipitation-qPCR, CUT&Tag, and biochemical assays. Human myeloid-derived suppressor cells (MDSCs) sorted from peripheral blood mononuclear cells were co-cultured with NSCLC cells and then assessed for their immunosuppressive activity on T-cells. Mouse Lewis lung carcinoma (LLC) cells with PD-L1 overexpression or knockdown were subcutaneously injected into wild-type or PD-1-knockout C57BL/6 mice in the presence of IL-6 and/or PD-1 blockade.
Results In the ICI cohort with RNA-seq data, the IL-6/Jak/Stat3 pathway was enriched, and IL-6 expression was higher in patients with PD-L1-high NSCLCs who did not respond to ICIs. In another cohort, a higher baseline serum IL-6 level was associated with poor clinical outcomes after ICI therapy. IL-6 expression and the IL-6/Jak/Stat3 pathway were enhanced in PD-L1-high NSCLCs in the ICI cohorts and The Cancer Genome Atlas analysis. IL-6 expression correlated positively with tumor-infiltrating MDSCs in NSCLCs. In NSCLC cells, PD-L1 activated Jak2/Stat3 signaling by binding to and inhibiting protein tyrosine phosphatase 1B. PD-L1 also bound to p-Stat3 in the nucleus, thus promoting the activity of p-Stat3 in the transcription of several cytokines (IL-6, TGF-β, TNF-α, IL-1β) and chemokines. PD-L1-overexpressing NSCLC cells enhanced the migration and immunosuppressive activity of human MDSCs in vitro, mediated by IL-6 and CXCL1. In both wild-type and PD-1-knockout mice, PD-L1-overexpressing LLC tumors were infiltrated by increased MDSCs with high immunosuppressive function, increased Tregs, and decreased granzyme B+ or IFNγ+ CD8 T-cells. These responses were mediated by IL-6 secreted from PD-L1-overexpressing tumor cells. Combined blockade of PD-1 and IL-6 was effective in tumor control and decreased MDSCs while increasing granzyme B+ or IFNγ+ CD8 T-cells.
Conclusions The tumor-cell-intrinsic function of PD-L1 drives immunosuppression and tumor progression through the PD-L1/Jak/Stat3/IL-6/MDSC axis. This pathway represents a potential therapeutic target to improve ICI efficacy in PD-L1-high NSCLC.
Methods Cohorts of NSCLC patients treated with ICI and public datasets were analyzed. PD-L1-overexpressing and PD-L1-knockdown NSCLC cells were submitted to RNA-seq, in vitro analyses, chromatin immunoprecipitation-qPCR, CUT&Tag, and biochemical assays. Human myeloid-derived suppressor cells (MDSCs) sorted from peripheral blood mononuclear cells were co-cultured with NSCLC cells and then assessed for their immunosuppressive activity on T-cells. Mouse Lewis lung carcinoma (LLC) cells with PD-L1 overexpression or knockdown were subcutaneously injected into wild-type or PD-1-knockout C57BL/6 mice in the presence of IL-6 and/or PD-1 blockade.
Results In the ICI cohort with RNA-seq data, the IL-6/Jak/Stat3 pathway was enriched, and IL-6 expression was higher in patients with PD-L1-high NSCLCs who did not respond to ICIs. In another cohort, a higher baseline serum IL-6 level was associated with poor clinical outcomes after ICI therapy. IL-6 expression and the IL-6/Jak/Stat3 pathway were enhanced in PD-L1-high NSCLCs in the ICI cohorts and The Cancer Genome Atlas analysis. IL-6 expression correlated positively with tumor-infiltrating MDSCs in NSCLCs. In NSCLC cells, PD-L1 activated Jak2/Stat3 signaling by binding to and inhibiting protein tyrosine phosphatase 1B. PD-L1 also bound to p-Stat3 in the nucleus, thus promoting the activity of p-Stat3 in the transcription of several cytokines (IL-6, TGF-β, TNF-α, IL-1β) and chemokines. PD-L1-overexpressing NSCLC cells enhanced the migration and immunosuppressive activity of human MDSCs in vitro, mediated by IL-6 and CXCL1. In both wild-type and PD-1-knockout mice, PD-L1-overexpressing LLC tumors were infiltrated by increased MDSCs with high immunosuppressive function, increased Tregs, and decreased granzyme B+ or IFNγ+ CD8 T-cells. These responses were mediated by IL-6 secreted from PD-L1-overexpressing tumor cells. Combined blockade of PD-1 and IL-6 was effective in tumor control and decreased MDSCs while increasing granzyme B+ or IFNγ+ CD8 T-cells.
Conclusions The tumor-cell-intrinsic function of PD-L1 drives immunosuppression and tumor progression through the PD-L1/Jak/Stat3/IL-6/MDSC axis. This pathway represents a potential therapeutic target to improve ICI efficacy in PD-L1-high NSCLC.
논문정보
- Research article
- 2025년 03월 (BRIC 등록일 2025-03-09)
- 국내 연구진
- 의약학 > 종양의학
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