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Alteration of the immunophenotype and cytokine profiles in patients affected by neuroendocrine neoplasms

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Abstract

Purpose

Neuroendocrine neoplasms (NENs) are tumors that arise from cells of the endocrine system and are most common in the gastrointestinal tract, the pancreas, and the lungs. Their incidence is rapidly increasing and the therapeutic options available are limited.

Methods

Since the immune system can interfere with tumor growth and response to therapy, using flow cytometry we investigated the immunophenotype in samples of peripheral blood leukocytes from patients with pancreatic (Pan-NENs) and pulmonary NENs (Lung-NENs). Moreover, we performed a multiplex analysis of 13 key cytokines and growth factors essential for the immune response in the plasma of NEN patients and controls.

Results

Patients presented with a higher percentage of granulocytes, a lower percentage of lymphocytes, and an increase in the granulocytes to lymphocytes ratio compared to healthy donors. These alterations were more marked in patients with metastasis. Somatostatin analogs (SSAs) restored the immunophenotype of patients to that seen in healthy donors. Finally, Pan-NEN patients showed a higher plasma concentration of IP-10, MCP-1, and IL-8 compared to healthy donors, suggesting a potential role for these cytokines as diagnostic biomarkers.

Conclusion

This study highlighted differences in the immunophenotype of patients with Pan- and Lung-NENs compared to healthy individuals; these alterations were partially restored by therapy.

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Data availability

The data that support the findings of this study are available upon reasonable request in the Zenodo repository (https://zenodo.org/record/6621996#.Yqb2_xrP3IU).

References

  1. A. Dasari, C. Shen, D. Halperin, B. Zhao, S. Zhou, Y. Xu, T. Shih, J.C. Yao, JAMA Oncol. 3, 1335 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  2. I. Uri, S. Avniel-Polak, D.J. Gross, S. Grozinsky-Glasberg, Curr. Treat. Options Oncol. 18, 72 (2017)

    Article  PubMed  Google Scholar 

  3. W.T. Zandee, W.W. de Herder, Neuroendocrinology 106, 357 (2018)

    Article  CAS  PubMed  Google Scholar 

  4. J.A. Chan, M.H. Kulke, Curr. Treat. Options Oncol. 12, 136 (2011)

    Article  PubMed  Google Scholar 

  5. J.C. Yao, A.T. Phan, V. Jehl, G. Shah, F. Meric-Bernstam, Cancer Res 73, 1449 (2013)

    Article  CAS  PubMed  Google Scholar 

  6. T.R. Halfdanarson, K.G. Rabe, J. Rubin, G.M. Petersen, Ann. Oncol. 19, 1727 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. M. Schiavo Lena, S. Partelli, P. Castelli, V. Andreasi, C.E. Smart, E. Pisa, M. Bartolomei, E. Bertani, G. Zamboni, M. Falconi, C. Doglioni, Endocr. Pathol. 31, 119 (2020)

    Article  CAS  PubMed  Google Scholar 

  8. K. Öberg, P. Hellman, P. Ferolla, M. Papotti, Ann. Oncol. 23, vii120 (2012)

    Article  PubMed  Google Scholar 

  9. M.H. Kulke, M.H. Shah, A.B. Benson Iii, E. Bergsland, J.D. Berlin, L.S. Blaszkowsky, L. Emerson, P.F. Engstrom, P. Fanta, T. Giordano, W.S. Goldner, T.R. Halfdanarson, M.J. Heslin, F. Kandeel, P.L. Kunz, B.W. Kuvshinoff Ii, C. Lieu, J.F. Moley, G. Munene, V.G. Pillarisetty, L. Saltz, A.J. Sosa, J.R. Strosberg, J. Vauthey, C. Wolfgang, J.C. Yao, J. Burns, D. Freedman-Cass, JNCCN-J. Natl. Compr. Cancer Netw. 13, 78 (2015)

    Article  CAS  Google Scholar 

  10. J. Hallet, C.H.L. Law, M. Cukier, R. Saskin, N. Liu, S. Singh, Cancer 121, 589 (2015)

    Article  PubMed  Google Scholar 

  11. H. Ungefroren, S. Sebens, D. Seidl, H. Lehnert, R. Hass, Cell Commun. Signal. 9, 18 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. X. Zheng, K. Turkowski, J. Mora, B. Brüne, W. Seeger, A. Weigert, R. Savai, Oncotarget 8, 48436 (2017)

  13. G.W. Tormoen, M.R. Crittenden, M.J. Gough, Adv. Radiat. Oncol. 3, 520 (2018)

    Article  PubMed  PubMed Central  Google Scholar 

  14. W.H. Fridman, F. Pagès, C. Saut̀s-Fridman, J. Galon, Nat. Rev. Cancer 12, 298 (2012)

    Article  CAS  PubMed  Google Scholar 

  15. A. Mantovani, P. Romero, A.K. Palucka, F.M. Marincola, Lancet 371, 771 (2008)

    Article  CAS  PubMed  Google Scholar 

  16. D. Hanahan, R.A. Weinberg, Cell 144, 646 (2011)

    Article  CAS  PubMed  Google Scholar 

  17. R.M. Slominski, C. Raman, J.Y. Chen, A.T. Slominski, Trends Neurosci. 46, 263 (2023)

    Article  CAS  PubMed  Google Scholar 

  18. M. Yamaguchi, S. Okamura, T. Yamaji, M. Iwasaki, S. Tsugane, V. Shetty, T. Koizumi, PLoS One 14, 1 (2019)

    Google Scholar 

  19. G. Shetty, G.M. Beasley, S. Sparks, M. Barfield, M. Masoud, P.J. Mosca, S.K. Pruitt, A.K.S. Salama, C. Chan, D.S. Tyler, K.J. Weinhold, Ann. Surg. Oncol. 20, 1128 (2013)

    Article  PubMed  PubMed Central  Google Scholar 

  20. B.E. Lippitz, R.A. Harris, Oncoimmunology 5, 1 (2016)

    Article  Google Scholar 

  21. K. Kawaguchi, M. Sakurai, Y. Yamamoto, E. Suzuki, M. Tsuda, T.R. Kataoka, M. Hirata, M. Nishie, T. Nojiri, M. Kumazoe, K. Saito, M. Toi, Sci. Rep. 9, 2924 (2019)

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  22. W.H. Zhang, W.Q. Wang, H.L. Gao, X.J. Yu, L. Liu, Biochim. Biophys. Acta - Rev. Cancer 1872, 188311 (2019)

  23. M. Cives, E. Pelle, D. Quaresmini, F.M. Rizzo, M. Tucci, F. Silvestris, Neuroendocrinology 109, 83 (2019)

    Article  CAS  PubMed  Google Scholar 

  24. C.S. Ferreira-Facio, C. Milito, V. Botafogo, M. Fontana, L.S. Thiago, E. Oliveira, A.S. da Rocha-Filho, F. Werneck, D.N. Forny, S. Dekermacher, A.P. de Azambuja, S.E. Ferman, P.A.S. de Faria, M.G.P. Land, A. Orfao, E.S. Costa, PLoS One 8, e55534 (2013)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  25. A.D. Herrera-Martínez, J. Hofland, L.J. Hofland, T. Brabander, F.A.L.M. Eskens, M.A. Gálvez Moreno, R.M. Luque, J.P. Castaño, W.W. de Herder, R.A. Feelders, Drugs 79, 21 (2019)

    Article  PubMed  Google Scholar 

  26. L. Lee, T. Ito, R.T. Jensen, Expert Opin. Pharmacother. 19, 909 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. C. Ménétrier-Caux, I. Ray-Coquard, J.-Y. Blay, C. Caux, J. Immunother. Cancer 7, 85 (2019)

    Article  PubMed  PubMed Central  Google Scholar 

  28. F. Bösch, K. Brüwer, A. Altendorf-Hofmann, C.J. Auernhammer, C. Spitzweg, C.B. Westphalen, S. Boeck, G. Schubert-Fritschle, J. Werner, V. Heinemann, T. Kirchner, M. Angele, T. Knösel, Endocr. Relat. Cancer 26, 293 (2019)

    Article  PubMed  Google Scholar 

  29. P.F. Wang, T.J. Wang, Y.K. Yang, K. Yao, Z. Li, Y.M. Li, C.-X.X. Yan, J. Neurooncol. 139, 89 (2018)

    Article  PubMed  Google Scholar 

  30. J.Q. Lu, B. Adam, A.S. Jack, A. Lam, R.W. Broad, C.L. Chik, Endocr. Pathol. 26, 263 (2015)

    Article  CAS  PubMed  Google Scholar 

  31. D. Takahashi, M. Kojima, T. Suzuki, M. Sugimoto, S. Kobayashi, S. Takahashi, M. Konishi, N. Gotohda, M. Ikeda, T. Nakatsura, A. Ochiai, M. Nagino, Sci. Rep. 8, 13166 (2018)

  32. M.N. Aparicio-Pagés, H.W. Verspaget, A.S. Peña, J.B.M.J. Jansen, C.B.H.W. Lamers, Neuropeptides 20, 1 (1991)

    Article  PubMed  Google Scholar 

  33. M. Gharagozloo, H. Kalantari, A. Rezaei, M.R. Maracy, M. Salehi, A. Bahador, N. Hassannejad, M. Narimani, M.H. Sanei, B. Bayat, H. Ghazanfari, Bratislava Med. J. 116, 296 (2015)

    Article  CAS  Google Scholar 

  34. I. Caras, A. Grigorescu, C. Stavaru, D.L. Radu, I. Mogos, G. Szegli, A. Salageanu, Cancer Immunol. Immunother. 53, 1146 (2004)

    Article  CAS  PubMed  Google Scholar 

  35. N. Tsavaris, C. Kosmas, M. Vadiaka, P. Kanelopoulos, D. Boulamatsis, Br. J. Cancer 87, 21 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. M.E. Shaul, Z.G. Fridlender, Nat. Rev. Clin. Oncol. 16, 601 (2019)

    Article  PubMed  Google Scholar 

  37. A. Ocana, C. Nieto-Jiménez, A. Pandiella, A.J. Templeton, Mol. Cancer 16, 1 (2017)

    Article  Google Scholar 

  38. H. Li, Q. Liu, S. Liang, P. Yao, J. Lv, G. Wang, R. Tang, T. Zhao, J. Li, L. Xu, L. Ma, R. Wang, Transl. Cancer Res. 10, 288 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. L.-L. Cao, J. Lu, J.-X. Lin, C.-H. Zheng, P. Li, J.-W. Xie, J.-B. Wang, Q.-Y. Chen, M. Lin, R.-H. Tu, C.-M. Huang, World J. Gastroenterol. 23, 8376 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  40. A.M. Zawada, K.S. Rogacev, B. Rotter, P. Winter, R.-R. Marell, D. Fliser, G.H. Heine, Blood 118, e50 (2011)

    Article  CAS  PubMed  Google Scholar 

  41. K.L. Wong, J.J.-Y. Tai, W.-C. Wong, H. Han, X. Sem, W.-H. Yeap, P. Kourilsky, S.-C. Wong, Blood 118, e16 (2011)

    Article  CAS  PubMed  Google Scholar 

  42. D. Schauer, P. Starlinger, C. Reiter, N. Jahn, P. Zajc, E. Buchberger, T. Bachleitner-Hofmann, M. Bergmann, A. Stift, T. Gruenberger, C. Brostjan, PLoS One 7, 1 (2012)

    Article  Google Scholar 

  43. Y. Song, Q. Zhou, H. Zhu, Y. Jing, X. Zhang, Y. Yang, Q. Hu, X. Huang, Y. Ni, J. Oral Pathol. Med. 47, 923 (2018)

    Article  CAS  PubMed  Google Scholar 

  44. M. Pavel, K. Öberg, M. Falconi, E.P. Krenning, A. Sundin, A. Perren, A. Berruti, Ann. Oncol. 31, 844 (2020)

    Article  CAS  PubMed  Google Scholar 

  45. M. Gomes-Porras, J. Cárdenas-Salas, C. Álvarez-Escolá, Int. J. Mol. Sci. 21, 1 (2020)

    Article  Google Scholar 

  46. M. Cigrovski Berković, T. Catela Ivković, J. Marout, V. Zjačić-Rotkvić, S. Kapitanović, DNA Cell Biol. 31, 531 (2012)

    Article  PubMed  PubMed Central  Google Scholar 

  47. E. Giannetta, A. La Salvia, L. Rizza, G. Muscogiuri, S. Campione, C. Pozza, A.A. Li. Colao, A. Faggiano, Front. Endocrinol. (Lausanne). 12, 672499 (2021)

  48. S.L. Deshmane, S. Kremlev, S. Amini, B.E. Sawaya, J. Interf. Cytokine Res. 29, 313 (2009)

    Article  CAS  Google Scholar 

  49. S.Y. Lim, A.E. Yuzhalin, A.N. Gordon-Weeks, R.J. Muschel, Oncotarget 7, 28697 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  50. Q. Yang, N. Guo, Y. Zhou, J. Chen, Q. Wei, M. Han, Acta Pharm. Sin. B 10, 2156 (2020)

  51. P. Marques, S. Barry, E. Carlsen, D. Collier, A. Ronaldson, S. Awad, N. Dorward, J. Grieve, N. Mendoza, S. Muquit, A.B. Grossman, F. Balkwill, M. Korbonits, Acta Neuropathol. Commun. 7, 172 (2019)

  52. F. Gotsch, R. Romero, L. Friel, J.P. Kusanovic, J. Espinoza, O. Erez, N.G. Than, P. Mittal, S. Edwin, B.H. Yoon, C.J. Kim, S. Mazaki-Tovi, T. Chaiworapongsa, S.S. Hassan, J. Matern. Neonatal. Med. 20, 777 (2007)

    Article  CAS  Google Scholar 

  53. B. Mlecnik, M. Tosolini, P. Charoentong, A. Kirilovsky, G. Bindea, A. Berger, M. Camus, M. Gillard, P. Bruneval, W. Fridman, F. Pagès, Z. Trajanoski, J. Galon, Gastroenterology 138, 1429 (2010)

    Article  CAS  PubMed  Google Scholar 

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Funding

This research was funded by The Ministry of Education, University and Research (grant numbers PRIN 2017Z3N3YC and PRIN 2022CZR88M).

Author information

Author notes

  1. These authors contributed equally: Eleonora Vitali, Andrea G. Lania

Authors and Affiliations

  1. Laboratory of Cellular and Molecular Endocrinology, IRCCS Humanitas Research Hospital, 20089, Rozzano, Italy

    Ilena Boemi, Giampaolo Trivellin & Eleonora Vitali

  2. Endocrinology, Diabetology, and Andrology Unit, IRCCS Humanitas Research Hospital, 20089, Rozzano, Italy

    Sara Piccini, Elisabetta Lavezzi, Gherardo Mazziotti & Andrea G. Lania

  3. Flow Cytometry Core, IRCCS Humanitas Research Hospital, 20089, Rozzano, Italy

    Federico S. Colombo

  4. Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, 20089, Rozzano, Italy

    Valeria Smiroldo

  5. Department of Biomedical Sciences, Humanitas University, 20072, Pieve Emanuele, Italy

    Alessandro Zerbi, Giovanni Capretti, Marco Alloisio, Giampaolo Trivellin, Gherardo Mazziotti & Andrea G. Lania

  6. Pancreas Surgery Unit, IRCCS Humanitas Research Hospital, 20089, Rozzano, Italy

    Alessandro Zerbi & Giovanni Capretti

  7. Thoracic Surgery Unit, IRCCS Humanitas Research Hospital, 20089, Rozzano, Italy

    Marco Alloisio

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  1. Ilena Boemi
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Contributions

Conceptualization, I.B.; Data curation, I.B., E.V., S.P., V.S., A.Z., G.C., M.A., and A.L.; Formal analysis, I.B., E.V., and F.C.; Funding acquisition, A.L.; Investigation, I.B.; Methodology, I.B.; Project administration, G.M., and A.L.; Resources, S.P., V.S., A.Z., G.C., M.A., E.L., G.M., and A.L.; Supervision, G.M., E.V., and A.L.; Visualization, E.V., F.C., G.T. and E.L.; Writing – review & editing E.V., S.P., I.B., F.C., V.S., G.T., and A.L.; All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Eleonora Vitali.

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This work has been approved for publication by all authors.

Ethical approval

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Independent Ethical Committee of IRCCS Humanitas Research Hospital, Rozzano (Milan) (study no. 1937, authorization data: 6 February 2018).

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Boemi, I., Piccini, S., Colombo, F.S. et al. Alteration of the immunophenotype and cytokine profiles in patients affected by neuroendocrine neoplasms. Endocrine 83, 810–823 (2024). https://doi.org/10.1007/s12020-023-03563-9

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