Abstract
IFN-γ-induced PD-L1 expression represents the existence of tumor-specific T cells, which predicts high-response rate to anti-PD-1/L1 therapy, but loss-of-function of IFN signals (e.g., JAK mutation) induces adaptive immune resistance in patients with low-response rate. Interferon regulatory factors (IRF) are frequently epigenetic silenced in carcinogenesis, while the role of methylation in anti-PD-1/L1 therapy remains unclear. We here investigated the methylation status of IFN-γ related genes IRF1/8 and IFN-α/β-related genes IRF3/7 in lung cancer tissues and found that only highly methylated IRF1 and 7 negatively correlated to cd274 (coding PD-L1) expression, similar to JAK mutation. Interestingly, decitibine (DAC) as methylation inhibitor could hypomethylate IRF1/7 to restore PD-L1 level. Meanwhile, IRF7 enhanced constitutive PD-L1 expression, which was independent of IFN-γ though directly promote transcription of PD-L1, leading to abrogating cytotoxic T lymphocytes (CTLs) generation which could be restored by anti-PD-L1 antibody, or siRNA-IRF7. The supplement of DAC to anti-PD-1 therapy in vivo improve the efficiency of anti-tumor with less methylated IRF1/7, more interferon-related genes expression (e.g., CXCL9) and IFN-γ/CD8+ T-cells infiltrations, suggesting that additional treatment of DAC could rescue the ability to response to IFN in lung cancer patients with anti-PD-1/L1 therapy resistance.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Naylor EC, Desani JK, Chung PK. Targeted therapy and immunotherapy for lung cancer. Surg Oncol Clin N Am. 2016;25:601–9.
Socinski MA, Obasaju C, Gandara D, Hirsch FR, Bonomi P, Bunn P, et al. Clinicopathologic features of advanced squamous NSCLC. J Thorac Oncol. 2016;11:1411–22.
Sacher AG, Gandhi L. Biomarkers for the clinical use of PD-1/PD-L1 inhibitors in non-small-cell lung cancer: a review. JAMA Oncol. 2016;2:1217–22.
Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14:847–56.
McLaughlin J, Han G, Schalper KA, Carvajal-Hausdorf D, Pelekanou V, Rehman J, et al. Quantitative assessment of the heterogeneity of PD-L1 expression in non-small-cell lung cancer. JAMA Oncol. 2016;2:46–54.
Ribas A, Hu-Lieskovan S. What does PD-L1 positive or negative mean? J Exp Med. 2016;213:2835–40.
Akbay EA, Koyama S, Carretero J, Altabef A, Tchaicha JH, Christensen CL, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov. 2013;3:1355–63.
Shin DS, Zaretsky JM, Escuin-Ordinas H, Garcia-Diaz A, Hu-Lieskovan S, Kalbasi A, et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov. 2017;7:188–201.
Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4:127ra137.
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. New Engl J Med. 2015;373:23–34.
Ma D, Jiang C, Hu X, Liu H, Li Q, Li T, et al. Methylation patterns of the IFN-gamma gene in cervical cancer tissues. Sci Rep. 2014;4:6331.
Ortmann CA, Burchert A, Holzle K, Nitsche A, Wittig B, Neubauer A, et al. Down-regulation of interferon regulatory factor 4 gene expression in leukemic cells due to hypermethylation of CpG motifs in the promoter region. Nucleic Acids Res. 2005;33:6895–905.
Yamashita M, Toyota M, Suzuki H, Nojima M, Yamamoto E, Kamimae S, et al. DNA methylation of interferon regulatory factors in gastric cancer and noncancerous gastric mucosae. Cancer Sci. 2010;101:1708–16.
Dunn GP, Sheehan KC, Old LJ, Schreiber RD. IFN unresponsiveness in LNCaP cells due to the lack of JAK1 gene expression. Cancer Res. 2005;65:3447–53.
Lee SJ, Jang BC, Lee SW, Yang YI, Suh SI, Park YM, et al. Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-gamma-induced upregulation of B7-H1 (CD274). FEBS Lett. 2006;580:755–62.
Breugom AJ, Swets M, Bosset JF, Collette L, Sainato A, Cionini L, et al. Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data. Lancet Oncol. 2015;16:200–7.
Ding L, Ren J, Zhang D, Li Y, Huang X, Ji J. et al. The TLR3 agonist inhibit drug efflux and sequentially consolidates low-dose cisplatin-based chemoimmunotherapy while reducing side effects. Mol Cancer Ther. 2017;16:1068–79.
Mehta A, Dobersch S, Romero-Olmedo AJ, Barreto G. Epigenetics in lung cancer diagnosis and therapy. Cancer Metastas- Rev. 2015;34:229–41.
Wrangle J, Wang W, Koch A, Easwaran H, Mohammad HP, Vendetti F, et al. Alterations of immune response of non-small cell lung cancer with azacytidine. Oncotarget. 2013;4:2067–79.
Zhang Z, Chang CK, He Q, Guo J, Tao Y, Wu LY, et al. Increased PD-1/STAT1 ratio may account for the survival benefit in decitabine therapy for lower risk myelodysplastic syndrome. Leuk Lymphoma. 2017;58:969–78.
Yang H, Bueso-Ramos C, DiNardo C, Estecio MR, Davanlou M, Geng QR, et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia. 2014;28:1280–8.
Liu J, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, Hetuin D, et al. Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-{gamma} and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood. 2007;110:296–304.
Acknowledgements
This work was supported by the Natural Science Foundation of Guangxi (2016GXNSFAA380138) and Science Research and Technology Development Plan of Guangxi (2015BC12007).
Author contributions
Q.L., H.W., A.L., J.S., and Z.D. designed the experiments. Development of methodology: Q.L., H.W., A.L., Y.X., L.T., Q.C., C.Z., and Y.G. Q.L., H.W., J.S., and Z.D. analyzed the data and wrote the manuscript with all approving the final version.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Lai, Q., Wang, H., Li, A. et al. Decitibine improve the efficiency of anti-PD-1 therapy via activating the response to IFN/PD-L1 signal of lung cancer cells. Oncogene 37, 2302–2312 (2018). https://doi.org/10.1038/s41388-018-0125-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41388-018-0125-3
This article is cited by
-
Unraveling T cell exhaustion in the immune microenvironment of osteosarcoma via single-cell RNA transcriptome
Cancer Immunology, Immunotherapy (2024)
-
DNA hypermethylation driven by DNMT1 and DNMT3A favors tumor immune escape contributing to the aggressiveness of adrenocortical carcinoma
Clinical Epigenetics (2023)
-
Targeting CXCL9/10/11–CXCR3 axis: an important component of tumor-promoting and antitumor immunity
Clinical and Translational Oncology (2023)
-
Targeting PD-1/PD-L1 pathway in myelodysplastic syndromes and acute myeloid leukemia
Experimental Hematology & Oncology (2022)
-
The developing landscape of combinatorial therapies of immune checkpoint blockade with DNA damage repair inhibitors for the treatment of breast and ovarian cancers
Journal of Hematology & Oncology (2021)