Abstract
Purpose
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).
Methods
Thirty-nine patients from our department were studied for immunohistochemical NGF, PD-1, and PD-L1 expression and clinico-pathological correlation.
Results
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.
Conclusions
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.
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References
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
Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392:245–252. https://doi.org/10.1038/32588
Bichakjian CK et al (2014) Merkel cell carcinoma, version 1.2014. J Natl Compr Cancer Net JNCCN 12:410–424
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
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
Coit DG (2001) Merkel cell carcinoma. Ann Surg Oncol 8:99S-102S
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
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
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
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
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
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
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
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
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
Levi-Montalcini R (1987) The nerve growth factor 35 years later. Science 237:1154–1162
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
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
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
Miller RW, Rabkin CS (1999) Merkel cell carcinoma and melanoma: etiological similarities and differences. Cancer Epidemiol Biomark 8:153–158
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
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
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
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
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
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
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
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
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
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
Xie H et al (2014) TERT promoter mutations and gene amplification: Promoting TERT expression in Merkel. Cell Carcinoma Oncotarget 5:10048–10057
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
Acknowledgements
The authors thank Hans-Michael Behrens and Thomas Langkamp for advice regarding statistical calculations and Arne Voss for help in image editing.
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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.
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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
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DOI: https://doi.org/10.1007/s00432-018-2657-x