Vol 53, No 3 (2019)
Research paper
Published online: 2019-06-12
Submitted: 2018-11-18
Accepted: 2019-03-11
Get Citation

Autoimmune response in lung cancer patients with neurological paraneoplastic syndromes

Sławomir Michalak, Tomasz Piorunek, Mikołaj Zaborowski, Joanna Rybacka-Mossakowska, Patrycja Stefens-Stawna, Alicja Kalinowska-Łyszczarz, Wojciech Kozubski, Halina Batura-Gabryel
DOI: 10.5603/PJNNS.a2019.0025
·
Pubmed: 31187476
·
Neurol Neurochir Pol 2019;53(3):217-226.

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Vol 53, No 3 (2019)
Research paper
Published online: 2019-06-12
Submitted: 2018-11-18
Accepted: 2019-03-11

Abstract

Aim of the study. The aim of this study was to evaluate granzyme B, perforin and FasL expression in peripheral blood mononuclear cells (PBMCs) in lung cancer patients and in paraneoplastic neurological syndromes (PNS).

Clinical rationale for the study. Cellular immune response is activated as part of anti-tumour reaction of the malignancy-bearing host. Paraneoplastic neurological syndromes (PNS) are defined as indirect effects of cancer on the nervous system and are considered immune-mediated. Such stimulation of the immune system may limit the aggressiveness of cancer and the development of metastasis, and thereby improve survival. Granzyme B and perforin pathway, and Fas ligand (FasL) – Fas receptor interaction play an important role in cytotoxic response.

Materials and Methods. Fifty-two patients were included in the study: 28 subjects with PNS and 24 subjects with lung cancer. PNS cases were diagnosed according to the Graus criteria. The presence of onconeural antibodies (anti-Hu/anti-Ri/anti-Yo/anti-Ma/Ta/anti-CV2/anti-amphiphysin/anti-myelin/anti-neuroendothelium/anti-MAG/anti-GAD) was detected with indirect immunofluorescence and confirmed with Line Blotting. The expression of granzyme B, perforin and FasL was detected in PBMCs with ELISA.

Results. PPBMC-FasL expression was increased in lung cancer compared to other patient groups. The granzyme to FasL ratio was significantly higher in lung cancer patients with peripheral than with central PNS involvement. In a multiple regression model, sex was an independent factor influencing PBMC expression of granzyme and perforin.

Conclusions. FasL expression in PBMCs is up-regulated in lung cancer patients. The interplay between granzyme B and FasL may be involved in the development of PNS at the level of the peripheral and the central nervous systems in different manners. Gender is associated with PBMC expression of granzyme B and perforin in lung cancer patients.

Clinical Implications. The novel findings that we report broaden the current knowledge on PNS pathomechanism, with aspects that have not been previously explored. Our findings provide a rationale for further exploration of the granzyme B/FasL pathway with regards to its potential diagnostic value. However, our study is preliminary and needs further research, especially in the context of the prognostic value of the proposed markers.

Abstract

Aim of the study. The aim of this study was to evaluate granzyme B, perforin and FasL expression in peripheral blood mononuclear cells (PBMCs) in lung cancer patients and in paraneoplastic neurological syndromes (PNS).

Clinical rationale for the study. Cellular immune response is activated as part of anti-tumour reaction of the malignancy-bearing host. Paraneoplastic neurological syndromes (PNS) are defined as indirect effects of cancer on the nervous system and are considered immune-mediated. Such stimulation of the immune system may limit the aggressiveness of cancer and the development of metastasis, and thereby improve survival. Granzyme B and perforin pathway, and Fas ligand (FasL) – Fas receptor interaction play an important role in cytotoxic response.

Materials and Methods. Fifty-two patients were included in the study: 28 subjects with PNS and 24 subjects with lung cancer. PNS cases were diagnosed according to the Graus criteria. The presence of onconeural antibodies (anti-Hu/anti-Ri/anti-Yo/anti-Ma/Ta/anti-CV2/anti-amphiphysin/anti-myelin/anti-neuroendothelium/anti-MAG/anti-GAD) was detected with indirect immunofluorescence and confirmed with Line Blotting. The expression of granzyme B, perforin and FasL was detected in PBMCs with ELISA.

Results. PPBMC-FasL expression was increased in lung cancer compared to other patient groups. The granzyme to FasL ratio was significantly higher in lung cancer patients with peripheral than with central PNS involvement. In a multiple regression model, sex was an independent factor influencing PBMC expression of granzyme and perforin.

Conclusions. FasL expression in PBMCs is up-regulated in lung cancer patients. The interplay between granzyme B and FasL may be involved in the development of PNS at the level of the peripheral and the central nervous systems in different manners. Gender is associated with PBMC expression of granzyme B and perforin in lung cancer patients.

Clinical Implications. The novel findings that we report broaden the current knowledge on PNS pathomechanism, with aspects that have not been previously explored. Our findings provide a rationale for further exploration of the granzyme B/FasL pathway with regards to its potential diagnostic value. However, our study is preliminary and needs further research, especially in the context of the prognostic value of the proposed markers.

Get Citation

Keywords

lung cancer, paraneoplastic neurological syndromes, cytotoxicity, onconeural antibodies, Fas ligand, granzyme B, perforin

About this article
Title

Autoimmune response in lung cancer patients with neurological paraneoplastic syndromes

Journal

Neurologia i Neurochirurgia Polska

Issue

Vol 53, No 3 (2019)

Pages

217-226

Published online

2019-06-12

DOI

10.5603/PJNNS.a2019.0025

Pubmed

31187476

Bibliographic record

Neurol Neurochir Pol 2019;53(3):217-226.

Keywords

lung cancer
paraneoplastic neurological syndromes
cytotoxicity
onconeural antibodies
Fas ligand
granzyme B
perforin

Authors

Sławomir Michalak
Tomasz Piorunek
Mikołaj Zaborowski
Joanna Rybacka-Mossakowska
Patrycja Stefens-Stawna
Alicja Kalinowska-Łyszczarz
Wojciech Kozubski
Halina Batura-Gabryel

References (25)
  1. Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. 2004; 75(8): 1135–1140.
  2. Stefens-Stawna P, Piorunek T, Gabryel-Batura H, et al. Neurological paraneoplastic syndromes in lung cancer patients. Adv Exp Med Biol. 2013; 756: 333–339.
  3. Albert ML, Darnell RB. Paraneoplastic neurological degenerations: keys to tumour immunity. Nat Rev Cancer. 2004; 4(1): 36–44.
  4. Darnell RB, DeAngelis LM. Regression of small-cell lung carcinoma in patients with paraneoplastic neuronal antibodies. Lancet. 1993; 341(8836): 21–22.
  5. Tanaka M, Tanaka K, Onodera O, et al. Trial to establish an animal model of paraneoplastic cerebellar degeneration with anti-Yo antibody. Clinical Neurology and Neurosurgery. 1995; 97(1): 95–100.
  6. Blumenthal DT, Salzman KL, Digre KB, et al. Early pathologic findings and long-term improvement in anti-Ma2-associated encephalitis. Neurology. 2006; 67(1): 146–149.
  7. Aye MM, Kasai T, Tashiro Y, et al. CD8 positive T-cell infiltration in the dentate nucleus of paraneoplastic cerebellar degeneration. J Neuroimmunol. 2009; 208(1-2): 136–140.
  8. Psimaras D, Carpentier AF, Rossi C, et al. PNS Euronetwork. Cerebrospinal fluid study in paraneoplastic syndromes. J Neurol Neurosurg Psychiatry. 2010; 81(1): 42–45.
  9. Metkar SS, Menaa C, Pardo J, et al. Human and mouse granzyme A induce a proinflammatory cytokine response. Immunity. 2008; 29(5): 720–733.
  10. Bolitho P, Voskoboinik I, Trapani JA, et al. Apoptosis induced by the lymphocyte effector molecule perforin. Curr Opin Immunol. 2007; 19(3): 339–347.
  11. Cullen SP, Brunet M, Martin SJ. Granzymes in cancer and immunity. Cell Death Differ. 2010; 17(4): 616–623.
  12. Wang LF, Wang F, Li JT, et al. Ectopically expressed perforin-1 is proapoptotic in tumor cell lines by increasing caspase-3 activity and the nuclear translocation of cytochrome C. PLoS One. 2012; 7(7): e40639.
  13. Scaffidi C, Fulda S, Srinivasan A, et al. Two CD95 (APO-1/Fas) signaling pathways. EMBO J. 1998; 17(6): 1675–1687.
  14. Maher S, Toomey D, Condron C, et al. Activation-induced cell death: the controversial role of Fas and Fas ligand in immune privilege and tumour counterattack. Immunol Cell Biol. 2002; 80(2): 131–137.
  15. Rieux-Laucat F, Le Deist F, Hivroz C, et al. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science. 1995; 268(5215): 1347–1349.
  16. Wada A, Tada Y, Kawamura K, et al. The effects of FasL on inflammation and tumor survival are dependent on its expression levels. Cancer Gene Ther. 2007; 14(3): 262–267.
  17. Niehans GA, Brunner T, Frizelle SP, et al. Human lung carcinomas express Fas ligand. Cancer Res. 1997; 57(6): 1007–1012.
  18. LOWRY OH, ROSEBROUGH NJ, FARR AL, et al. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951; 193(1): 265–275.
  19. Bien CG, Vincent A, Barnett MH, et al. Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain. 2012; 135(Pt 5): 1622–1638.
  20. Tanaka M, Maruyama Y, Sugie M, et al. Cytotoxic T cell activity against peptides of Hu protein in anti-Hu syndrome. J Neurol Sci. 2002; 201(1-2): 9–12.
  21. Szabo A, Dalmau J, Manley G, et al. HuD, a paraneoplastic encephalomyelitis antigen, contains RNA-binding domains and is homologous to Elav and Sex-lethal. Cell. 1991; 67(2): 325–333.
  22. Roberts WK, Deluca IJ, Thomas A, et al. Patients with lung cancer and paraneoplastic Hu syndrome harbor HuD-specific type 2 CD8+ T cells. J Clin Invest. 2009; 119(7): 2042–2051.
  23. Michalak S, Wender M, Michałowska-Wender G. Cachexia--induced cerebellar degeneration: involvement of serum TNF and MCP-1 in the course of experimental neoplastic disease. Acta Neurobiol Exp (Wars). 2006; 66(2): 113–122.
  24. Bernal F, Graus F, Pifarré A, et al. Immunohistochemical analysis of anti-Hu-associated paraneoplastic encephalomyelitis. Acta Neuropathol. 2002; 103(5): 509–515.
  25. Tüzün E, Zhou L, Baehring JM, et al. Evidence for antibody-mediated pathogenesis in anti-NMDAR encephalitis associated with ovarian teratoma. Acta Neuropathol. 2009; 118(6): 737–743.

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