Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Co-expression of NGF and PD-L1 on tumor-associated immune cells in the microenvironment of Merkel cell carcinoma



Merkel cell carcinoma (MCC) is a malignant neuroendocrine skin tumor with known viral association. The microenvironment and its interaction with the tumor via the programmed cell death protein 1 (PD-1) pathway are crucial for response to anti-PD-1/anti-PD-L1 treatments. However, not all patients respond, which is suggestive of additional mechanisms for tumor growth and/or persistence. We previously detected tropomyosin receptor kinase A (TrkA) expression on MCC tumor cells and, therefore, gained interest in the expression of its ligand nerve growth factor (NGF).


Thirty-nine patients from our department were studied for immunohistochemical NGF, PD-1, and PD-L1 expression and clinico-pathological correlation.


PD-L1 was expressed on the tumor cells in 42%. In 95%, PD-L1 expression was also found on CD68+ spindle cells at the tumor border, which co-expressed NGF in 71%. 66% contained PD-1+ tumor infiltrating lymphocytes. PD-1, PD-L1, and NGF expression seems to correlate with a worse outcome.


The present study shows that PD-L1 and NGF are co-expressed on spindle cells in the microenvironment. The expression of NGF might be a link of the microenvironment to the TrkA-positive tumor cells. Whether this mechanism is critical for tumor growth and lack of response to anti-PD-1/L1 treatment has to be investigated in further studies.

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

Fig. 1
Fig. 2
Fig. 3


  1. Amatu A, Sartore-Bianchi A, Siena S (2016) NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open 1:e000023. https://doi.org/10.1136/esmoopen-2015-000023

  2. Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392:245–252. https://doi.org/10.1038/32588

  3. Bichakjian CK et al (2014) Merkel cell carcinoma, version 1.2014. J Natl Compr Cancer Net JNCCN 12:410–424

  4. Boger C, Behrens HM, Mathiak M, Kruger S, Kalthoff H, Rocken C (2016) PD-L1 is an independent prognostic predictor in gastric cancer of western patients. Oncotarget 7:24269–24283. https://doi.org/10.18632/oncotarget.8169

  5. Bradshaw RA, Pundavela J, Biarc J, Chalkley RJ, Burlingame AL, Hondermarck H (2015) NGF and ProNGF: regulation of neuronal and neoplastic responses through receptor signaling. Adv Biol Regul 58:16–27. https://doi.org/10.1016/j.jbior.2014.11.003

  6. Coit DG (2001) Merkel cell carcinoma. Ann Surg Oncol 8:99S-102S

  7. Drilon A et al. (2017) A next-generation TRK kinase inhibitor overcomes acquired resistance to prior TRK kinase inhibition in patients with TRK fusion-positive solid tumors. Cancer Discov. https://doi.org/10.1158/2159-8290.CD-17-0507

  8. Freidin MM (2001) Antibody to the extracellular domain of the low affinity NGF receptor stimulates p75(NGFR)-mediated apoptosis in cultured sympathetic neurons. J Neurosci Res 64:331–340

  9. Kaplan DR, Hempstead BL, Martin-Zanca D, Chao MV, Parada LF (1991) The trk proto-oncogene product: a signal transducing receptor for nerve growth factor. Science 252:554–558

  10. Kaufman HL et al (2016) Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 17:1374–1385. https://doi.org/10.1016/S1470-2045(16)30364-3

  11. Kenchappa RS, Tep C, Korade Z, Urra S, Bronfman FC, Yoon SO, Carter BD (2010) p75 neurotrophin receptor-mediated apoptosis in sympathetic neurons involves a biphasic activation of JNK and up-regulation of tumor necrosis factor-alpha-converting enzyme/ADAM17. J Biol Chem 285:20358–20368. https://doi.org/10.1074/jbc.M109.082834

  12. Kluger HM et al (2015) Characterization of PD-L1 expression and associated T-cell infiltrates in metastatic melanoma samples from variable anatomic sites. Clin Cancer Res 21:3052–3060. https://doi.org/10.1158/1078-0432.CCR-14-3073

  13. Kostine M, Cleven AH, de Miranda NF, Italiano A, Cleton-Jansen AM, Bovee JV (2016) Analysis of PD-L1, T-cell infiltrate and HLA expression in chondrosarcoma indicates potential for response to immunotherapy specifically in the dedifferentiated subtype. Modern Pathol https://doi.org/10.1038/modpathol.2016.108

  14. Lambiase A et al (1997) Human CD4+ T cell clones produce and release nerve growth factor and express high-affinity nerve growth factor receptors. J Allergy Clin Immunol 100:408–414

  15. Lemos BD et al (2010) Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system. J Am Acad Dermatol 63:751–761. https://doi.org/10.1016/j.jaad.2010.02.056

  16. Levi-Montalcini R (1987) The nerve growth factor 35 years later. Science 237:1154–1162

  17. Lipson EJ et al (2013) PD-L1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus and overall survival. Cancer Immunol Res 1:54–63. https://doi.org/10.1158/2326-6066.CIR-13-0034

  18. Marlin MC, Li G (2015) Biogenesis and function of the NGF/TrkA signaling endosome. Int Rev cell Mol Biol 314:239–257. https://doi.org/10.1016/bs.ircmb.2014.10.002

  19. Meffert MK, Chang JM, Wiltgen BJ, Fanselow MS, Baltimore D (2003) NF-kappa B functions in synaptic signaling and behavior. Nat Neurosci 6:1072–1078. https://doi.org/10.1038/nn1110

  20. Miller RW, Rabkin CS (1999) Merkel cell carcinoma and melanoma: etiological similarities and differences. Cancer Epidemiol Biomark 8:153–158

  21. Mitteldorf C, Berisha A, Tronnier M, Pfaltz MC, Kempf W (2017) PD-1 and PD-L1 in neoplastic cells and the tumor microenvironment of Merkel cell carcinoma. J Cutan Pathol 44:740–746. https://doi.org/10.1111/cup.12973

  22. Narisawa Y, Koba S, Inoue T, Nagase K (2015) Histogenesis of pure and combined Merkel cell carcinomas: an immunohistochemical study of 14 cases. J Dermatol. https://doi.org/10.1111/1346-8138.12808

  23. Parra ER et al. (2016) Image analysis-based assessment of PD-L1 and tumor-associated immune cells density supports distinct intratumoral microenvironment groups in non-small cell lung carcinoma patients. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-15-2443

  24. Patnaik A et al (2015) Phase I study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res 21:4286–4293. https://doi.org/10.1158/1078-0432.CCR-14-2607

  25. Riley JL (2009) PD-1 signaling in primary T cells. Immunol Rev 229:114–125. https://doi.org/10.1111/j.1600-065X.2009.00767.x

  26. Sakamoto Y, Kitajima Y, Edakuni G, Hamamoto T, Miyazaki K (2001) Combined evaluation of NGF and p75NGFR expression is a biomarker for predicting prognosis in human invasive ductal breast carcinoma. Oncol Rep 8:973–980

  27. Santos-Juanes J et al (2015) Merkel cell carcinoma and Merkel cell polyomavirus: a systematic review and meta-analysis. Br J Dermatol 173:42–49. https://doi.org/10.1111/bjd.13870

  28. Schadendorf D et al (2017) Immune evasion mechanisms and immune checkpoint inhibition in advanced merkel. Cell Carcinoma Oncoimmunol 6:e1338237. https://doi.org/10.1080/2162402X.2017.1338237

  29. Van Gele M, Leonard JH, Van Roy N, Cook AL, De Paepe A, Speleman F (2001) Frequent allelic loss at 10q23 but low incidence of PTEN mutations in Merkel cell carcinoma. Int J Cancer Journal international du cancer 92:409–413

  30. Wehkamp U, Stern S, Kruger S, Hauschild A, Rocken C, Egberts F (2017) Tropomyosin receptor kinase A expression on merkel cell carcinoma cells. JAMA Dermatol. https://doi.org/10.1001/jamadermatol.2017.2495

  31. Xie H et al (2014) TERT promoter mutations and gene amplification: Promoting TERT expression in Merkel. Cell Carcinoma Oncotarget 5:10048–10057

  32. Zhu ZW, Friess H, Wang L, Bogardus T, Korc M, Kleeff J, Buchler MW (2001) Nerve growth factor exerts differential effects on the growth of human pancreatic cancer cells. Clin Cancer Res 7:105–112

Download references


The authors thank Hans-Michael Behrens and Thomas Langkamp for advice regarding statistical calculations and Arne Voss for help in image editing.



Author information

Correspondence to Ulrike Wehkamp.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wehkamp, U., Stern, S., Krüger, S. et al. Co-expression of NGF and PD-L1 on tumor-associated immune cells in the microenvironment of Merkel cell carcinoma. J Cancer Res Clin Oncol 144, 1301–1308 (2018). https://doi.org/10.1007/s00432-018-2657-x

Download citation


  • NGF
  • Merkel cell carcinoma
  • PD-L1
  • PD-1
  • TrkA