Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Comment
  • Published:

Transcriptional regulation of the immune checkpoints PD-1 and CTLA-4

Cellular & Molecular Immunology volume 19, pages 861–862 (2022)Cite this article

Subjects

Immunotherapy targeting immune checkpoints (ICs) has revolutionized the field of cancer treatment. ICs are a group of proteins that provide stimulatory or inhibitory signals to regulate T-cell activation, tolerance, and exhaustion. To date, some immune checkpoint inhibitors (ICIs) targeting TIM-3, LAG-3, TIGIT, and VISTA are under investigation for their clinical applications. However, only ICIs against CTLA-4, PD-1, and PD-L1 are approved by the FDA and widely used as first-line or second-line treatments for multiple cancer types. CTLA-4 and PD-1 are coinhibitory receptors that are mainly expressed by T cells. PD-L1 is a PD-1 ligand expressed by tumor cells [1]. Tumor-infiltrating T cells with high expression of CTLA-4 and PD-1 do not respond effectively. ICIs can restore the antitumor effects of tumor-infiltrating T cells by releasing inhibitory obstacles. Ipilimumab, an antagonistic antibody against CTLA-4, was first used in patients with metastatic melanoma. To date, seven ICIs of the PD-1/PD-L1 pathway have been approved, including four anti-PD-1 and three anti-PD-L1 monoclonal antibodies [2]. Despite promising clinical benefits, only some cancer patients experience good responses. Furthermore, some responders develop resistance after treatment. Nevertheless, the underlying mechanism has not been fully studied. Since the PD-1 and CTLA-4 signaling pathways play important roles in regulating T-cell exhaustion and peripheral tolerance, understanding the mechanisms regulating PD-1 and CTLA-4 expression and identifying their regulatory transcription factors are helpful for developing novel therapeutic approaches for cancers, autoimmune diseases, and chronic infections.

PD-1 expression is upregulated after T-cell activation. PD-1 binds to the ligands PD-L1 or PD-L2 to transmit inhibitory signals. PD-1 is encoded by the gene Pdcd1. Two important elements have been identified at the Pdcd1 locus: conserved region B (CR-B) and conserved region C (CR-C) [3]. CR-B is located at −100 bp of Pdcd1, while CR-C is located at −1.1 kb. Both regions contribute to Pdcd1 transcription. CR-B enhances Pdcd1 transcription and exhibits robust transcriptional activation in cooperation with CR-C. However, CR-C does not have independent activity, although this region is essential for responses to T-cell activation signals. There are several transcription factor-binding sites in CR-B, CR-C, and other regions.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

References

  1. Zhang H, Dai Z, Wu W, Wang Z, Zhang N, Zhang L, et al. Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer. J Exp Clin Cancer Res. 2021;40:184.

    Article  CAS  Google Scholar 

  2. Kaushik I, Ramachandran S, Zabel C, Gaikwad S, Srivastava SK. The evolutionary legacy of immune checkpoint inhibitors. Semin. Cancer Biol. (2022). https://doi.org/10.1016/j.semcancer.2022.03.020

  3. Chi Z, Lu Y, Yang Y, Li B, Lu P. Transcriptional and epigenetic regulation of PD-1 expression. Cell Mol Life Sci. 2021;78:3239–46.

    Article  CAS  Google Scholar 

  4. Oestreich KJ, Yoon H, Ahmed R, Boss JM. NFATc1 regulates PD-1 expression upon T cell activation. J Immunol. 2008;181:4832–9.

    Article  CAS  Google Scholar 

  5. Mathieu M, Cotta-Grand N, Daudelin JF, Thebault P, Labrecque N. Notch signaling regulates PD-1 expression during CD8(+) T-cell activation. Immunol Cell Biol. 2013;91:82–8.

    Article  CAS  Google Scholar 

  6. Austin JW, Lu P, Majumder P, Ahmed R, Boss JM. STAT3, STAT4, NFATc1, and CTCF regulate PD-1 through multiple novel regulatory regions in murine T cells. J Immunol. 2014;192:4876–86.

    Article  CAS  Google Scholar 

  7. Staron MM, Gray SM, Marshall HD, Parish IA, Chen JH, Perry CJ, et al. The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8(+) T cells during chronic infection. Immunity. 2014;41:802–14.

    Article  CAS  Google Scholar 

  8. Xiao G, Deng A, Liu H, Ge G, Liu X. Activator protein 1 suppresses antitumor T-cell function via the induction of programmed death 1. Proc Natl Acad Sci USA. 2012;109:15419–24.

    Article  CAS  Google Scholar 

  9. Kao C, Oestreich KJ, Paley MA, Crawford A, Angelosanto JM, Ali MA, et al. Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection. Nat Immunol. 2011;12:663–71.

    Article  CAS  Google Scholar 

  10. Lu P, Youngblood BA, Austin JW, Mohammed AU, Butler R, Ahmed R, et al. Blimp-1 represses CD8 T cell expression of PD-1 using a feed-forward transcriptional circuit during acute viral infection. J Exp Med. 2014;211:515–27.

    Article  CAS  Google Scholar 

  11. Gibson HM, Mishra A, Chan DV, Hake TS, Porcu P, Wong HK. Impaired proteasome function activates GATA3 in T cells and upregulates CTLA-4: relevance for Sezary syndrome. J investigative Dermatol. 2013;133:249–57.

    Article  CAS  Google Scholar 

  12. Guo J, Xue Z, Ma R, Yi W, Hui Z, Guo Y, et al. The transcription factor Zfp281 sustains CD4(+) T lymphocyte activation through directly repressing Ctla-4 transcription. Cell Mol Immunol. 2020;17:1222–32.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (32030035, 31870874, 32100693, 32000623) and Zhejiang Provincial Key Project of Research and Development (2019C03043).

Author information

Authors and Affiliations

  1. Institute of Immunology and Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China

    Jing Guo, Zhonghui Xue & Lie Wang

  2. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA

    Jing Guo

  3. Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China

    Zhonghui Xue

  4. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, 311121, China

    Lie Wang

Authors
  1. Jing Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhonghui Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lie Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lie Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guo, J., Xue, Z. & Wang, L. Transcriptional regulation of the immune checkpoints PD-1 and CTLA-4. Cell Mol Immunol 19, 861–862 (2022). https://doi.org/10.1038/s41423-022-00877-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-022-00877-y

Search

Advanced search

Quick links