Skip to main content
PMC home page
Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 1993 Mar;36(2):108–114. doi: 10.1007/BF01754410

Depressed monocyte polarization and clustering of dendritic cells in patients with head and neck cancer: In vitro restoration of this immunosuppression by thymic hormones

Maarten P R Tas 1,✉, Peter J Simons 1, Fons J M Balm 2, Hemmo A Drexhage 1
PMCID: PMC11038702  PMID: 8425208

Abstract

The in vitro restoring effects of a thymic hormone preparation, TP-1, on defective monocyte and dendritic cell function in patients with head and neck squamous cell carcinoma (HNSCC) have been examined. TheN-formylmethionyl-leucyl-phenylalanine(fMLF)-induced polarization of monocytes isolated from the peripheral blood was significantly lower (a mean of 19%) than the polarization of monocytes isolated from healthy controls (a mean of 33%). After the in vitro addition of TP-1 this defective polarization was improved to the normal value of 33% polarized monocytes. The capability of dendritic cells prepared from the blood to form cellular clusters with allogeneic cells was impaired in 26/44 patients. In vitro addition of TP-1 again had restoring effects. The original defective dendritic cell clustering of 97 clusters/six microscopic fields (mean) was improved to a value of 121 clusters. The defects in monocyte polarization and clustering of dendritic cells could be ascribed to the presence in serum of a tumor-derived low-molecularmass factor low-M r factor; <25 kDa) sharing structural homology with p15E, the capsular protein of murine and feline leukemogenic retroviruses. The incubation of low-M r factor from the serum of HNSCC patients with healthy donor monocytes resulted in a significantly higher inhibition of fMLF-induced monocyte polarization than did incubation with control low-M r factor (a mean of 42 versus 16% inhibition). This suppressive effect of patient low-M r factor was abrogated with a mixture of two monoclonal antibodies against p15E as well as with TP-1. The observations here reported on the in vitro effects of TP-1 on depressed monocyte and dendritic cell function in HNSCC have provided one of the rationales for a TP-1 therapeutic pilot trial recently started in HNSCC patients.

Key words: Squamous cell carcinoma, Monocytes, Dendritic cells, p15E antigen, Thymostimulin, TP-1

References

  • 1.Aiuti F, Fiorilli M, Schirrmacher V. Effect of thymus factor on human precursor T lymphocytes. Clin Exp Immunol. 1975;20:499–499. [Google Scholar]
  • 2.Austyn JM, Weinstein DE, Steinman RM. Clustering with dendritic cells precedes and is essential for T cell proliferation in a mitogenesis model. Immunology. 1988;63:691–691. [PMC free article] [PubMed] [Google Scholar]
  • 3.Balm AJM, Drexhage HA, von Blomberg-van der Flier BME, Weltevreden EF, Veldhuizen BW, Mullink H, Snow GB. Mononuclear phagocyte function in head and neck cancer. The chemotactic responsiveness of blood monocytes in correlation between the histological grade of the tumor and the infiltration of these cells into the tumor area. Cancer. 1984;54:1010–1010. doi: 10.1002/1097-0142(19840915)54:6<1010::aid-cncr2820540613>3.0.co;2-n. [DOI] [PubMed] [Google Scholar]
  • 4.Bergesi G, Falchetti R. Chemical characterization and biological activity of a new thymic extract. Folia Allergol Immunol Clin. 1977;21:204–204. [Google Scholar]
  • 5.Bergfelt L, Bucana C, Kripke ML. Alterations in Langerhans cells during growth of transplantable murine tumors. J Invest Dermatol. 1988;91:129–129. doi: 10.1111/1523-1747.ep12464151. [DOI] [PubMed] [Google Scholar]
  • 6.Bier J, Nicklish U. Investigations of unspecific immunoreactivity in patients with head and neck carcinoma. Arch Otorhinolaryngol. 1981;232:145–145. doi: 10.1007/BF00505034. [DOI] [PubMed] [Google Scholar]
  • 7.Bröcker EB, Zwadlo G, Holzmann B, Macher E, Sorg C. Inflammatory cell infiltrates in human melanoma at different stages of tumor progression. Int J Cancer. 1988;41:562–562. doi: 10.1002/ijc.2910410415. [DOI] [PubMed] [Google Scholar]
  • 8.Bugelski PJ, Corwin SP, North SM, Kirsch RL, Nicholson GL, Poste G. Macrophage contact of spontaneous metastases at different stages of growth. Cancer Res. 1987;47:4141–4141. [PubMed] [Google Scholar]
  • 9.Bugelski PJ, Kirsch R, Buscarino C, Corwin SP, Poste G. Recruitment of exogenous macrophages into metastases at different stages of tumor growth. Cancer Immunol Immunother. 1987;24:93–93. doi: 10.1007/BF00205584. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Cameron DJ, Stromberg BV. The ability of macrophages from head and neck cancer patients to kill tumor cells. Effect of prostaglandin inhibitors on cytotoxicity. Cancer. 1984;54:2403–2403. doi: 10.1002/1097-0142(19841201)54:11<2403::aid-cncr2820541116>3.0.co;2-f. [DOI] [PubMed] [Google Scholar]
  • 11.Catalona WJ, Sample WF, Chretien PB. Lymphocyte reactivity in cancer patients: correlation with tumor histology and clinical stage. Cancer. 1973;31:65–65. doi: 10.1002/1097-0142(197301)31:1<65::aid-cncr2820310109>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
  • 12.Cianciolo GJ, Snyderman R. Monocyte responsiveness to chemotactic stimuli is a property of a subpopulation of cells that can respond to multiple chemoattractants. J Clin Invest. 1981;67:60–60. doi: 10.1172/JCI110033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Cianciolo GJ, Hunter J, Silva J, Haskill JS, Snyderman R. Inhibitors of monocyte responses to chemotaxins are present in human cancerous effusions and react with monoclonal antibodies to the P15(E) structural protein of retroviruses. J Clin Invest. 1981;68:831–831. doi: 10.1172/JCI110338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Cianciolo GJ, Copeland TD, Oroszlan S, Snyderman R. Inhibition of lymphocyte proliferation by a synthetic peptide homologous to retroviral envelope proteins. Science. 1985;230:453–453. doi: 10.1126/science.2996136. [DOI] [PubMed] [Google Scholar]
  • 15.Dardenne M, Bach JF. Thymic hormone in the treatment of cancer. Immun Cancer. 1989;2:363–363. [PubMed] [Google Scholar]
  • 16.Falchetti R, Bergesi G, Eshkol A, Cafiero C, Adorini L, Caprino L. Pharmacological and biological properties of a calf thymus extract (TP-1) Drugs Exp Clin Res. 1977;3:39–39. [Google Scholar]
  • 17.Fidler IJ. Macrophage therapy of cancer metastasis. Metastases, Ciba Found Symp. 1988;141:211–211. doi: 10.1002/9780470513736.ch12. [DOI] [PubMed] [Google Scholar]
  • 18.Gottlieb RA, Lennarz WJ, Knowles RD, Cianciolo GJ, Dinarello CA, Lachman LB, Kleinerman ES. Synthetic peptide corresponding to a conserved domain of the retroviral protein p15E blocks IL-1-mediated signal transduction. J Immunol. 1989;142:4321–4321. [PubMed] [Google Scholar]
  • 19.Guyere LA, Barfoot R, Denham S, Hall JG. Immunity to a syngeneic sarcoma induced in rats by dendritic lymph cells exposed to the tumour either in vivo or in vitro. Br J Cancer. 1987;55:17–17. doi: 10.1038/bjc.1987.4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Harrell RA, Cianciolo GJ, Copeland TD, Oroszlan S, Snyderman R. Suppression of the respiratory burst of human monocytes by a synthetic peptide homologous to envelope proteins of human and animal retroviruses. J Immunol. 1986;136:3517–3517. [PubMed] [Google Scholar]
  • 21.Harris DT, Cianciolo GJ, Snyderman R, Argov S, Koren HS. Inhibition of human natural killer cell activity by a synthetic peptide homologous to a conserved region in the retroviral protein, p15E. J Immunol. 1987;138:889–889. [PubMed] [Google Scholar]
  • 22.Helmberg A, Fassler R, Geley S, Johrer K, Kroemer G, Bock G, Kofler R. Glucocorticoid-regulated gene expression in the immune system. Analysis of glucocorticoid-regulated transcripts from the mouse macrophage-like cell line P388D1. J Immunol. 1990;145:4332–4332. [PubMed] [Google Scholar]
  • 23.Inaba K, Steinman RM. Accessory cell-T lymphocyte interactions. Antigen-dependent and antigen-independent clustering. J Exp Med. 1986;163:247–247. doi: 10.1084/jem.163.2.247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Inaba K, Steinman RM. Monoclonal antibodies to LFA-1 and to CD4 inhibit the mixed leukocyte reaction after the antigen-dependent clustering of dendritic cells and T lymphocytes. J Exp Med. 1987;165:1403–1403. doi: 10.1084/jem.165.5.1403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Iwata T, Incefy GS, Cunningham-Rundles S, Smithwick E, Geller N, O'Reilly R, Good RA. Circulating thymic hormone activity in patients with primary and secondary immunodeficiency diseases. Am. J. Med. 1981;71:385–385. doi: 10.1016/0002-9343(81)90164-9. [DOI] [PubMed] [Google Scholar]
  • 26.Iwata T, Incefy GS, Cunningham-Rundles S, Dardenne M, Kapoor N, Kirkpatrick D, O'Reilly RJ. Circulating thymic hormone levels in severe combined immunodeficiency. Clin Exp Immunol. 1983;53:1–1. [PMC free article] [PubMed] [Google Scholar]
  • 27.Jenkins VK, Ray P, Ellis HN, Griffiths CM, Perry RR, Olsen MH. Lymphocyte response in patients with head and neck cancer. Arch Otolaryngol. 1976;102:596–596. doi: 10.1001/archotol.1976.00780150064003. [DOI] [PubMed] [Google Scholar]
  • 28.Kabel PJ, de Haan-Meulman M, Voorbij HAM, Kleingeld M, Knol EF, Drexhage HA. Accessory cells with a morphology and marker pattern of dendritic cells can be obtained from elutriatorpurified blood monocyte fractions. An enhancing effect of metrizamide in this differentiation. Immunobiology. 1989;179:395–395. doi: 10.1016/S0171-2985(89)80044-0. [DOI] [PubMed] [Google Scholar]
  • 29.Kleinerman ES, Lachman LB, Knowles RD, Snyderman R, Cianciolo GJ. A synthetic peptide homologous to the envelope proteins of retroviruses inhibits monocyte-mediated killing by inactivating interleukin 1. J Immunol. 1987;139:2329–2329. [PubMed] [Google Scholar]
  • 30.Lafrado LJ, Lewis MG, Mathes LE, Olsen RG. Suppression of in vitro neutrophil function by feline leukaemia virus (FeLV) and purified FeLV-p15E. J Gen Virol. 1987;68:507–507. doi: 10.1099/0022-1317-68-2-507. [DOI] [PubMed] [Google Scholar]
  • 31.Lichtenstein A, Zighelboim J, Dorey F, Brossman S, Fahey JL. Comparison of immune derangements in patients with different malignancies. Cancer. 1980;45:2090–2090. doi: 10.1002/1097-0142(19800415)45:8<2090::aid-cncr2820450816>3.0.co;2-o. [DOI] [PubMed] [Google Scholar]
  • 32.Mathes LE, Olsen RG, Hebebrand LC, Hoover EA, Schaller JP. Abrogation of lymphocyte blastogenesis by a feline leukaemia virus protein. Nature. 1978;274:684–684. doi: 10.1038/274687a0. [DOI] [PubMed] [Google Scholar]
  • 33.Mitani M, Cianciolo GJ, Snyderman R, Yasuda M, Good RA, Day NK. Suppressive effect on polyclonal B-cell activation of a synthetic peptide homologous to a transmembrane component of oncogenic retroviruses. Proc Natl Acad Sci USA. 1987;84:237–237. doi: 10.1073/pnas.84.1.237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Mullink H, von Blomberg-van der Flier M, Wilders MM, Drexhage HA, Alons CL. A simple cytochemical method for distinguishing EAC rosettes formed by lymphocytes and monocytes. J Immunol Methods. 1979;29:133–133. doi: 10.1016/0022-1759(79)90062-0. [DOI] [PubMed] [Google Scholar]
  • 35.Nomori H, Watanabe S, Nakajima T, Shimosato Y, Kameya T. Histiocytes in nasopharyngeal carcinoma in relation to prognosis. Cancer. 1986;57:100–100. doi: 10.1002/1097-0142(19860101)57:1<100::aid-cncr2820570121>3.0.co;2-x. [DOI] [PubMed] [Google Scholar]
  • 36.Orosz CG, Zinn NE, Olsen RG, Mathes LE. Retrovirus-mediated immunosuppression. I. FeLV-UV and specific FeLV proteins alter T lymphocyte behaviour by inducing hyporesponsiveness to lymphokines. J Immunol. 1985;134:3396–3396. [PubMed] [Google Scholar]
  • 37.Pertoft H, Johnsson A, Wärmegård B, Seljelid R. Separation of human monocytes on density gradients of Percoll. J Immunol Methods. 1980;33:221–221. doi: 10.1016/0022-1759(80)90209-4. [DOI] [PubMed] [Google Scholar]
  • 38.Pinsky CM, Oettgen HF, Domeiri A, Old LJ, Beatti EJ, Burchenal JH. Delayed type hypersensitivity reactions in patients with cancer. Proc Am Assoc Cancer Res. 1971;62:399–399. [Google Scholar]
  • 39.Ruegg CL, Monell CR, Strand M. Identification, using synthetic peptides, of the minimum amino acid sequence from the retroviral transmembrane protein required for inhibition of lymphoproliferation and its similarity to gp21 of human T-lymphotropic virus types I and II. J Virol. 1989;63:3250–3250. doi: 10.1128/jvi.63.8.3250-3256.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Scheeren RA, Koopman G, vd Baan S, Meyer CJLM, Pals SP. Adhesion receptors involved in early clustering of blood dendritic cells and T-lymphocytes. Eur J Immunol. 1991;21:1101–1101. doi: 10.1002/eji.1830210503. [DOI] [PubMed] [Google Scholar]
  • 41.Schmidt DM, Sidhu NK, Cianciolo GJ, Snyderman R. Recombinant hydrophilic region of murine retroviral p15E inhibits stimulated T-lymphocyte proliferation. Proc Natl Acad Sci USA. 1987;84:7290–7290. doi: 10.1073/pnas.84.20.7290. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Schroder S, Schwarz W, Rehpenning W, Loning T, Bocker W. Dendritic/Langerhans cells and prognosis in patients with papillary thyroid carcinomas. Immunocytochemical study of 106 thyroid neoplasms correlated to follow-up data. Am J Clin Pathol. 1988;89:295–295. doi: 10.1093/ajcp/89.3.295. [DOI] [PubMed] [Google Scholar]
  • 43.Tan IB, Drexhage HA, Scheper RJ, von Blomberg-van der Flier BME, de Haan-Meulman M, Snow GB, Balm AJM. Immunosuppressive retroviral p15E-related factors in head and neck carcinomas. Arch Otolaryngol Head Neck Surg. 1986;112:942–942. doi: 10.1001/archotol.1986.03780090038006. [DOI] [PubMed] [Google Scholar]
  • 44.Tan IB, Drexhage HA, Scheper RJ, von Blomberg-van der Flier BME, de Haan-Meulman M, Snow GB, Balm AJM. Defective monocyte chemotaxis in patients with head and neck cancer. Restoration after treatment. Arch Otolaryngol Head Neck Surg. 1986;112:541–541. doi: 10.1001/archotol.1986.03780050065011. [DOI] [PubMed] [Google Scholar]
  • 45.Tan IB, Drexhage HA, Mullink H, Henzen-Logmans SC, de Haan-Meulman M, Snow GB, Balm AJM. Immunohistochemical detection of retroviral p15E-related material in carcinomas of the head and neck. Otolaryngol Head Neck Surg. 1987;96:251–251. doi: 10.1177/019459988709600304. [DOI] [PubMed] [Google Scholar]
  • 46.Tas M, Leezenberg JA, Drexhage HA. Beneficial effects of the thymic hormone preparation thymostimulin in patients with defects in cell-mediated immunity and chronic purulent rhinosinusitis. A double-blind cross-over trial on improvements in monocyte polarization and clinical effects. Clin Exp Immunol. 1990;80:304–304. doi: 10.1111/j.1365-2249.1990.tb03286.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Tas M, de Haan-Meulman M, Kabel PJ, Drexhage HA. Defects in monocyte polarization and dendritic cell clustering in patients with Graves' disease. A putative role for a non-specific immunoregulatory factor related to p15E. Clin Endocrinol. 1991;34:441–441. doi: 10.1111/j.1365-2265.1991.tb00323.x. [DOI] [PubMed] [Google Scholar]
  • 48.Van de Plassche-Boers EM, Tas M, de Haan-Meulman M, Kleingeld M, Drexhage HA. Abnormal monocyte chemotaxis in patients with chronic purulent rhinosinusitis: an effect of retroviral p15E-related factors in serum. Clin Exp Immunol. 1988;73:348–348. [PMC free article] [PubMed] [Google Scholar]
  • 49.Walter RJ, Danielson JR. Characterization of formylpeptide chemoattractant binding on neutrophils and monocytes from patients with head and neck cancer. JNCI. 1987;78:61–61. doi: 10.1093/jnci/78.1.61. [DOI] [PubMed] [Google Scholar]

Articles from Cancer Immunology, Immunotherapy : CII are provided here courtesy of Springer

RESOURCES