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.

  • Article
  • Published:

CD147 regulates antitumor CD8+ T-cell responses to facilitate tumor-immune escape

Cellular & Molecular Immunology volume 18, pages 1995–2009 (2021)Cite this article

Subjects

Abstract

Negative regulation of antitumor T-cell-immune responses facilitates tumor-immune escape. Here, we show that deletion of CD147, a type I transmembrane molecule, in T cells, strongly limits in vivo tumor growth of mouse melanoma and lung cancer in a CD8+ T-cell-dependent manner. In mouse tumor models, CD147 expression was upregulated on CD8+ tumor-infiltrating lymphocytes (TILs), and CD147 was coexpressed with two immune-checkpoint molecules, Tim-3 and PD-1. Mining publicly available gene-profiling data for CD8+ TILs in tumor biopsies from metastatic melanoma patients showed a higher level of CD147 expression in exhausted CD8+ TILs than in other subsets of CD8+ TILs, along with expression of PD-1 and TIM-3. Additionally, CD147 deletion increased the abundance of TILs, cytotoxic effector function of CD8+ T cells, and frequency of PD-1+ CD8+ TILs, and partly reversed the dysfunctional status of PD-1+Tim-3+CD8+ TILs. The cytotoxic transcription factors Runx3 and T-bet mediation enhanced antitumor responses by CD147–/– CD8+ T cells. Moreover, CD147 deletion in T cells increased the frequency of TRM-like cells and the expression of the T-cell chemokines CXCL9 and CXCL10 in the tumor microenvironment. Analysis of tumor tissue samples from patients with non-small-cell lung cancer showed negative correlations between CD147 expression on CD8+ TILs and the abundance of CD8+ TILs, histological grade of the tumor tissue samples, and survival of patients with advanced tumors. Altogether, we found a novel function of CD147 as a negative regulator of antitumor responses mediated by CD8+ TILs and identified CD147 as a potential target for cancer immunotherapy.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Martinez-Lostao, L., Anel, A. & Pardo, J. How do cytotoxic lymphocytes kill cancer cells? Clin. Cancer Res. 21, 5047–5056 (2015).

    Article  CAS  PubMed  Google Scholar 

  2. Thommen, D. S. & Schumacher, T. N. T cell dysfunction in cancer. Cancer Cell 33, 547–562 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Li, H. et al. Dysfunctional CD8 T cells form a proliferative, dynamically regulated compartment within human melanoma. Cell 176, 775–789 (2019).

    Article  CAS  PubMed  Google Scholar 

  4. Gubin, M. M. et al. High-dimensional analysis delineates myeloid and lymphoid compartment remodeling during successful immune-checkpoint cancer therapy. Cell 175, 1014–1030 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chew, V. et al. Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses. Proc. Natl Acad. Sci. USA 114, E5900–E5909 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Khan, O. et al. TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion. Nature 571, 211–218 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wang, J. et al. Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3. Cell 176, 334–347 (2019).

    Article  CAS  PubMed  Google Scholar 

  8. Li, J. et al. Co-inhibitory molecule B7 superfamily member 1 expressed by tumor-infiltrating myeloid cells induces dysfunction of anti-tumor CD8(+) T cells. Immunity 48, 773–786 (2018).

    Article  CAS  PubMed  Google Scholar 

  9. Sun, C., Mezzadra, R. & Schumacher, T. N. Regulation and function of the PD-L1 checkpoint. Immunity 48, 434–452 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Pal, S. K. et al. Clinical cancer advances 2019: annual report on progress against cancer from the American Society of Clinical Oncology. J. Clin. Oncol. 37, 834–849 (2019).

    Article  PubMed  Google Scholar 

  11. Hashimoto, M. et al. CD8 T cell exhaustion in chronic infection and cancer: opportunities for interventions. Annu. Rev. Med. 69, 301–318 (2018).

    Article  CAS  PubMed  Google Scholar 

  12. Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168, 707–723 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wei, S. C. et al. Distinct cellular mechanisms underlie Anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell 170, 1120–1133 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Li, J., Ni, L. & Dong, C. Immune checkpoint receptors in cancer: redundant by design? Curr. Opin. Immunol. 45, 37–42 (2017).

    Article  CAS  PubMed  Google Scholar 

  16. Koch, C. et al. T cell activation-associated epitopes of CD147 in regulation of the T cell response, and their definition by antibody affinity and antigen density. Int. Immunol. 11, 777–786 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Weidle, U. H., Scheuer, W., Eggle, D., Klostermann, S. & Stockinger, H. Cancer-related issues of CD147. Cancer Genomics Proteom. 7, 157–169 (2010).

    CAS  Google Scholar 

  18. Solstad, T. et al. CD147 (Basigin/Emmprin) identifies FoxP3+CD45RO+CTLA4+-activated human regulatory T cells. Blood 118, 5141–5151 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. Landskron, J. & Tasken, K. CD147 in regulatory T cells. Cell. Immunol. 282, 17–20 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Renno, T. et al. A role for CD147 in thymic development. J. Immunol. 168, 4946–4950 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Arora, K. et al. Extracellular cyclophilins contribute to the regulation of inflammatory responses. J. Immunol. 175, 517–522 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Gwinn, W. M. et al. Novel approach to inhibit asthma-mediated lung inflammation using anti-CD147 intervention. J. Immunol. 177, 4870–4879 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Damsker, J. M. et al. Targeting the chemotactic function of CD147 reduces collagen-induced arthritis. Immunology 126, 55–62 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Agrawal, S. M., Silva, C., Wang, J., Tong, J. P. & Yong, V. W. A novel anti-EMMPRIN function-blocking antibody reduces T cell proliferation and neurotoxicity: relevance to multiple sclerosis. J. Neuroinflammation. 9, 64 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nabeshima, K. et al. Emmprin, a cell surface inducer of matrix metalloproteinases (MMPs), is expressed in T-cell lymphomas. J. Pathol. 202, 341–351 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Chen, X. et al. Inhibition of CD147 gene expression via RNA interference reduces tumor cell proliferation, activation, adhesion, and migration activity in the human Jurkat T-lymphoma cell line. Cancer Investig. 26, 689–697 (2008).

    Article  CAS  Google Scholar 

  27. Agrawal, S. M. et al. Extracellular matrix metalloproteinase inducer shows active perivascular cuffs in multiple sclerosis. Brain 136, 1760–1777 (2013).

    Article  PubMed  Google Scholar 

  28. Guo, N. et al. CD147 and CD98 complex-mediated homotypic aggregation attenuates the CypA-induced chemotactic effect on Jurkat T cells. Mol. Immunol. 63, 253–263 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Staffler, G. et al. Selective inhibition of T cell activation via CD147 through novel modulation of lipid rafts. J. Immunol. 171, 1707–1714 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Hu, J. et al. Involvement of HAb18G/CD147 in T cell activation and immunological synapse formation. J. Cell Mol. Med. 14, 2132–2143 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ruiz, S., Castro-Castro, A. & Bustelo, X. R. CD147 inhibits the nuclear factor of activated T-cells by impairing Vav1 and Rac1 downstream signaling. J. Biol. Chem. 283, 5554–5566 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Supper, V. et al. Association of CD147 and calcium exporter PMCA4 uncouples IL-2 expression from early TCR signaling. J. Immunol. 196, 1387–1399 (2016).

    Article  CAS  PubMed  Google Scholar 

  33. Yao, H. et al. Important functional roles of basigin in thymocyte development and T cell activation. Int. J. Biol. Sci. 10, 43–52 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Miller, B. C. et al. Subsets of exhausted CD8(+) T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol. 20, 326–336 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sade-Feldman, M. et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 175, 998–1013 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Thommen, D. S. et al. A transcriptionally and functionally distinct PD-1(+) CD8(+) T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade. Nat. Med. 24, 994–1004 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Singer, M. et al. A distinct gene module for dysfunction uncoupled from activation in tumor-infiltrating T cells. Cell 166, 1500–1511 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Cruz-Guilloty, F. et al. Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs. J. Exp. Med. 206, 51–59 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Milner, J. J. et al. Runx3 programs CD8(+) T cell residency in non-lymphoid tissues and tumours. Nature 552, 253–257 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hahn, J. N., Kaushik, D. K. & Yong, V. W. The role of EMMPRIN in T cell biology and immunological diseases. J. Leukoc. Biol. 98, 33–48 (2015).

    Article  CAS  PubMed  Google Scholar 

  41. Zhu, X., Song, Z., Zhang, S., Nanda, A. & Li, G. CD147: a novel modulator of inflammatory and immune disorders. Curr. Med. Chem. 21, 2138–2145 (2014).

    Article  CAS  PubMed  Google Scholar 

  42. Guo, N. et al. A critical epitope in CD147 facilitates memory CD4(+) T-cell hyper-activation in rheumatoid arthritis. Cell. Mol. Immunol. 16, 568–579 (2019).

    Article  CAS  PubMed  Google Scholar 

  43. Geng, J. J. et al. Targeting CD147 for T to NK lineage reprogramming and tumor therapy. EBioMedicine 20, 98–108 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Chen, R. et al. CD147 deficiency in T cells prevents thymic involution by inhibiting the EMT process in TECs in the presence of TGFbeta. Cell. Mol. Immunol. https://doi.org/10.1038/s41423-019-0353-7 (2020).

  45. Carow, B. et al. lck-driven Cre expression alters T cell development in the thymus and the frequencies and functions of peripheral T cell subsets. J. Immunol. 197, 2261–2268 (2017).

    Article  CAS  Google Scholar 

  46. Shan, Q. et al. The transcription factor Runx3 guards cytotoxic CD8(+) effector T cells against deviation towards follicular helper T cell lineage. Nat. Immunol. 18, 931–939 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ciucci, T., Vacchio, M. S. & Bosselut, R. A STAT3-dependent transcriptional circuitry inhibits cytotoxic gene expression in T cells. Proc. Natl Acad. Sci. USA 114, 13236–13241 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ganesan, A. P. et al. Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer. Nat. Immunol. 18, 940–950 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Nagarsheth, N., Wicha, M. S. & Zou, W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat. Rev. Immunol. 17, 559–572 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sharpe, A. H. & Pauken, K. E. The diverse functions of the PD1 inhibitory pathway. Nat. Rev. Immunol. 18, 153–167 (2018).

    Article  CAS  PubMed  Google Scholar 

  51. Chow, M. T. et al. Intratumoral activity of the CXCR3 chemokine system is required for the efficacy of anti-PD-1 therapy. Immunity 50, 1498–1512 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Schalper, K. A. et al. Objective measurement and clinical significance of TILs in non-small cell lung cancer. J. Natl. Cancer Inst. 107, dju435 (2015).

  53. Kurachi, M. et al. Optimized retroviral transduction of mouse T cells for in vivo assessment of gene function. Nat. Protoc. 12, 1980–1998 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kluger, H. M. et al. PD-L1 studies across tumor types, its differential expression and predictive value in patients treated with immune checkpoint inhibitors. Clin. Cancer Res. 23, 4270–4279 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank Xiwen Dong, Lijuan Wang, Qian He, and Xiaomin Li for their technical assistance and Jingmin Yu for assisting with mouse genotyping. This work was supported by grants from the National Natural Science Foundation of China (81572802), the National Basic Research Program of China (2015CB553700), and the Fourth Military Medical University Foundation for Development of Science and Technology (2019XB005).

Author information

Author notes

  1. These authors contributed equally: Yatong Chen, Jing Xu, Xiaodong Wu

Authors and Affiliations

  1. National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, 710032, Xi’an, China

    Yatong Chen, Jing Xu, Xiaodong Wu, Hui Yao, Zhou Yan, Ting Guo, Wenjing Wang, Peixiao Wang, Yu Li, Xiangmin Yang, Hao Li, Huijie Bian & Zhi-Nan Chen

  2. Medical Research Center, Southern University of Science and Technology Hospital, 518055, Shenzhen, China

    Jing Xu

  3. Center of Anesthesiology & Operation, Chinese PLA General Hospital, 100853, Beijing, China

    Xiaodong Wu

  4. Department of Radiation Oncology, First Peoples’ Hospital of Changzhou, Third Affiliated Hospital of Soochow University, 213000, Changzhou, China

    Hui Yao

  5. Department of Gastroenterology, Henan Children’s Hospital, 450018, Zhengzhou, China

    Peixiao Wang

Authors
  1. Yatong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaodong Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hui Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhou Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ting Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wenjing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peixiao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiangmin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Huijie Bian
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Zhi-Nan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Y.C., J.X., X.W., H.Y., Z.Y., W.W., P.W., T.G., Y.L., X.Y., and H.L. conducted the experiments and data analysis; J.X. and Z.-N.C. conceived the study and designed the experiments; Y.C., J.X., H.B., and Z.-N.C. discussed and interpreted the data; Y.C. and J.X. wrote the paper. All authors read and approved the final paper.

Corresponding authors

Correspondence to Jing Xu, Huijie Bian or Zhi-Nan Chen.

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

Chen, Y., Xu, J., Wu, X. et al. CD147 regulates antitumor CD8+ T-cell responses to facilitate tumor-immune escape. Cell Mol Immunol 18, 1995–2009 (2021). https://doi.org/10.1038/s41423-020-00570-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-020-00570-y

Keywords

This article is cited by

Search

Advanced search

Quick links