SpringerLink
Log in

PD-L2 overexpression on tumor-associated macrophages is one of the predictors for better prognosis in lung adenocarcinoma

  • Original Paper
  • Published:
Medical Molecular Morphology Aims and scope Submit manuscript

Abstract

Immunotherapies that target programmed cell death protein 1 (PD-1) signals are standard therapies for advanced-stage lung cancer, and the expression of programmed death-ligand 1 (PD-L1) in cancer tissue predicts immunotherapy efficacy. Although programmed death-ligand 2 (PD-L2) is expressed in cancer cells and macrophages, similar to PD-L1, its significance in lung cancer is unclear. Double immunohistochemistry analyses using anti-PD-L2 and anti-PU.1 antibodies were carried out on tissue array sections from 231 cases of lung adenocarcinoma, and PD-L2 expression in macrophages was evaluated. High PD-L2 expression in macrophages was associated with longer progression-free survival (PFS) and cancer-specific survival (CSS) and observed more often in females, non-heavy smokers, and patients with epidermal growth factor receptor (EGFR) mutations and those at a lower disease stage. Significant correlations were found more frequently in patients with EGFR mutations. Cell culture studies revealed that cancer cell-derived soluble factors induced PD-L2 overexpression in macrophages, suggesting the involvement of the JAK-STAT signaling pathway. The present findings suggest that PD-L2 expression in macrophages predicts PFS and CSS in lung adenocarcinoma without immunotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Availability of data and materials

The data presented in this study are available in this article and its supplementary materials.

Abbreviations

PD-1:

Programmed cell death protein 1

PD-L1:

Programmed cell death 1 ligand 1

JAK:

Janus kinase

STAT:

Signal transducer and activator of transcription

IHC:

Immunohistochemistry

PFS:

Progression-free survival

CSS:

Cancer-specific survival

EGFR:

Epidermal growth factor receptor

NSCLC:

Non-small-cell lung cancer

TAMs:

Tumor-associated macrophages

ELISA:

Enzyme-linked immunosorbent assay

CM:

Conditioned medium

References

  1. Hoffman PC, Mauer AM, Vokes EE (2000) Lung cancer. Lancet 355(9202):479–485

    Article  CAS  PubMed  Google Scholar 

  2. Thai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS (2021) Lung cancer. Lancet 398(10299):535–554

    Article  PubMed  Google Scholar 

  3. Reck M, Rodríguez-Abreu D, Robinson AG et al (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375(19):1823–1833

    Article  CAS  PubMed  Google Scholar 

  4. Hellmann MD, Paz-Ares L, Caro RB et al (2020) Atezolizumab for first-line treatment of PD-L1 selected patients with NSCLC. N Engl J Med 383(14):1328–1339

    Article  Google Scholar 

  5. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Topalian SL, Taube JM, Pardoll DM. Neoadjuvant checkpoint blockade for cancer immunotherapy. Science. 2020;367(6477):eaax0182.

  7. Koomen BM, Badrising SK, Heuvel MM, Willems SM (2020) Comparability of PD-L1 immunohistochemistry assays for non-small-cell lung cancer: a systematic review. Histopathology 76(6):793–802

    Article  PubMed  PubMed Central  Google Scholar 

  8. Herbst RS, Soria JC, Kowanetz M et al (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515(7528):563–567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shinchi Y, Komohara Y, Yonemitsu K et al (2019) Accurate expression of PD-L1/L2 in lung adenocarcinoma cells: a retrospective study by double immunohistochemistry. Cancer Sci 110(9):2711–2721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kozuma Y, Takada K, Toyokawa G, Kohashi K, Shimokawa M, Hirai F, Tagawa T, Okamoto T, Oda Y, Maehara Y (2018) Indoleamine 2,3-dioxygenase 1 and programmed cell death-ligand 1 co-expression correlates with aggressive features in lung adenocarcinoma. Eur J Cancer 101:20–29

    Article  CAS  PubMed  Google Scholar 

  11. Horlad H, Ma C, Yano H et al (2016) An IL-27/Stat3 axis induces expression of programmed cell death 1 ligands (PD-L1/2) on infiltrating macrophages in lymphoma. Cancer Sci 107(11):1696–1704

    Article  PubMed  PubMed Central  Google Scholar 

  12. Shinchi Y, Ishizuka S, Komohara Y et al (2022) The expression of PD-1 ligand 1 on macrophages and its clinical impacts and mechanisms in lung adenocarcinoma. Cancer Immunol Immunother 71(11):2645–2661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Komohara Y, Fujiwara Y, Ohnishi K, Takeya M (2016) Tumor-associated macrophages: potential therapeutic targets for anti-cancer therapy. Adv Drug Deliv Rev 99:180–185

    Article  CAS  PubMed  Google Scholar 

  14. Matsubara E, Komohara Y, Shinchi Y et al (2021) CD163-positive cancer cells are a predictor of a worse clinical course in lung adenocarcinoma. Pathol Int 71(10):666–673

    Article  CAS  PubMed  Google Scholar 

  15. Matsubara E, Komohara Y, Esumi S et al (2022) SPP1 derived from macrophages is associated with a worse clinical course and chemo-resistance in lung adenocarcinoma. Cancers 14(18):4374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Y, Kanda. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48(3):452–8.

  17. Kovaleva OV, Rashidova MA, Samoilova DV, Podlesnaya PA, Mochalnikova VV, Gratchev A (2020) Immunosuppressive phenotype of esophagus tumors stroma. Anal Cell Pathol 2020:5424780

    Article  Google Scholar 

  18. Wang Y, Du J, Gao Z, Sun H, Mei M, Wang Y, Ren Y, Zhou X. Evolving landscape of PD-L2: bring new light to checkpoint immunotherapy. Br J Cancer. 2022; Online ahead of print.

  19. Zerdes I, Matikas A, Bergh J, Rassidakis GZ, Foukakis T (2018) Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations. Oncogene 37(34):4639–4661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Matsusaka K, Fujiwara Y, Pan C et al (2021) α1-acid glycoprotein enhances the immunosuppressive and protumor functions of tumor-associated macrophages. Cancer Res 81(17):4545–4559

    Article  CAS  PubMed  Google Scholar 

  21. Umezu D, Okada N, Sakoda Y, Adachi K, Ojima T, Yamaue H, Eto M, Tamada K (2019) Inhibitory functions of PD-L1 and PD-L2 in the regulation of anti-tumor immunity in murine tumor microenvironment. Cancer Immunol Immunother 68(2):201–211

    Article  CAS  PubMed  Google Scholar 

  22. Yonemitsu K, Pan C, Fujiwara Y, Miyasato Y, Shiota T, Yano H, Hosaka S, Tamada K, Yamamoto Y, Komohara K (2022) GM-CSF derived from the inflammatory microenvironment potentially enhanced PD-L1 expression on tumor-associated macrophages in human breast cancer. Sci Rep 12(1):12007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li A, Wu W, Deng S et al (2022) Expression of programmed death ligand-2 is associated with prognosis in nasopharyngeal carcinoma microenvironment. J Cancer 13(15):3606–3614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Davidson C, Taggart D, Sims AH, Lonergan DW, Canel M, Serrels A (2022) FAK promotes stromal PD-L2 expression associated with poor survival in pancreatic cancer. Br J Cancer 127(10):1893–1905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Komohara Y, Fujiwara Y, Ohnishi K, Takeya M (2016) Tumor-associated macrophages: potential therapeutic targets for anti-cancer therapy. Adv Drug Deliv Rev 99(Pt B):180–185

    Article  CAS  PubMed  Google Scholar 

  26. Cassetta L, Pollard JW (2018) Targeting macrophages: therapeutic approaches in cancer. Nat Rev Drug Discov 17(12):887–904

    Article  CAS  PubMed  Google Scholar 

  27. Komohara Y, Kurotaki D, Tsukamoto H et al (2023) Involvement of protumor macrophages in breast cancer progression and characterization of macrophage phenotypes. Cancer Sci 114(6):2220–2229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Mr. Takenobu Nakagawa for the technical assistance.

Funding

This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Nos. 16H05162 and 20H03459).

Author information

Author notes

  1. Eri Matsubara and Yusuke Shinchi have equally contributed to this work.

Authors and Affiliations

  1. Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto Chuo-Ku, Kumamoto, 860-8556, Japan

    Eri Matsubara, Yoshihiro Komohara, Hiromu Yano, Cheng Pan & Yukio Fujiwara

  2. Department of Thoracic Surgery and Breast Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan

    Eri Matsubara, Yusuke Shinchi, Koei Ikeda & Makoto Suzuki

  3. Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto, Japan

    Yoshihiro Komohara

Authors
  1. Eri Matsubara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yusuke Shinchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoshihiro Komohara
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiromu Yano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cheng Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yukio Fujiwara
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Koei Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Makoto Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

EM: Data curation, Formal Analysis, Investigation, Software, Writing-original draft; YS: Investigation, Software, Visualization; YF: Conceptualization, Methodology, Validation; MS: Supervision; YK: Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Writing-review & editing. All authors read and approved the final version of the manuscript to be submitted.

Corresponding author

Correspondence to Yoshihiro Komohara.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

The study was approved by the Institutional Review Board of Kumamoto University (#1174), and conducted in accordance with the Declaration of Helsinki. Human macrophages were obtained from healthy donors in accordance with protocols approved by the Kumamoto University Hospital Review Board (approval No. 1169. No animal studies or registry/registration of this study was performed.

Consent to participate

Patient consent for inclusion in this study was waived by the Institutional Review Board of Kumamoto University (#2059) because the CSS and PFS data were obtained from previous reports [10, 15, 16]. Although all of the retrospective patient data were automatically included in the study, the patients were given the opportunity to refuse participation by opting out.

Consent for publication

Informed consent for publication was obtained from the relevant participants.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Matsubara, E., Shinchi, Y., Komohara, Y. et al. PD-L2 overexpression on tumor-associated macrophages is one of the predictors for better prognosis in lung adenocarcinoma. Med Mol Morphol 56, 250–256 (2023). https://doi.org/10.1007/s00795-023-00361-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00795-023-00361-0

Keywords

Search

Navigation