Low Dose of IL-12 Stimulates T Cell Response in Cultures of PBMCs Derived from Non Small Cell Lung Cancer Patients

DOI: 10.4236/jct.2012.324044   PDF   HTML     4,511 Downloads   8,300 Views   Citations


Cancer induces tolerance by suppressing immune function, modulating the T helper activity and causing an imbalance of cytokines produced by T cells. IL-12 is an immune regulatory cytokine with potent anti-tumor activity and its signalling network leads to polarization of na?ve CD4+ T cells into Th1. In pre-clinical studies, administration of recombinant IL-12 by intravenous injection or IL-12 plasmid DNA by intra-tumoral injection showed some anti-tumor effects, measurable immunological responses, but also important dose-dependent side effects. We investigated the ability of low doses of IL-12 to modulate the T cell subpopulations in cultures of PBMCs derived from Non Small Lung Cancer (NSCLC) patients and to induce lysis of lung adenocarcinoma cells by T cells. PBMCs were stimulated with different doses of IL-12 and T cell phenotype was evaluated. IL-12 at 0.01 pg/ml significantly increased the number of CD4 and CD8 T cells, in particular of CD4/IFNγ producing cells. IL-12 did not stimulate T regulatory, but it increased the lysis of lung adenocarcinoma cells induced by T cells. Our results showed that low doses of IL-12 modulates T cell sub-populations in vitro and it increased their lytic activity on adenocarcinoma cells, thus we hypothesize the use of low dose of IL-12 as a therapeutic tool against pathologies characterized by a T cell imbalance, in order to promote an immuno-modulation.

Share and Cite:

L. D’Amico, E. Ruffini, R. Ferracini and I. Roato, "Low Dose of IL-12 Stimulates T Cell Response in Cultures of PBMCs Derived from Non Small Cell Lung Cancer Patients," Journal of Cancer Therapy, Vol. 3 No. 4A, 2012, pp. 337-342. doi: 10.4236/jct.2012.324044.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] G. P. Dunn, L. J. Old and R. D. Schreiber, “The Three Es of Cancer Immunoediting,” Annual Review of Immunology, Vol. 22, 2004, pp. 329-360. doi:10.1146/annurev.immunol.22.012703.104803
[2] A. Nicolini, A. Carpi and G. Rossi, “Cytokines in Breast Cancer,” Cytokine & Growth Factor Reviews, Vol. 17, No. 5, 2006, pp. 325-337. doi:10.1016/j.cytogfr.2006.07.002
[3] A. Ben-Baruch, “Host Microenvironment in Breast Cancer Development: Inflammatory Cells, Cytokines and Chemokines in Breast Cancer Progression: Reciprocal Tumor-Microenvironment Interactions,” Breast Cancer Research, Vol. 5, No. 1, 2003, pp. 31-36. doi:10.1186/bcr554
[4] J. J. Bright and S. Sriram, “TGF-Beta Inhibits IL-12-Induced Activation of Jak-STAT Pathway in T Lymphocytes,” Journal of Immunology, Vol. 161, No. 4, 1998, pp. 1772-1777.
[5] C. Sudarshan, J. Galon, Y. Zhou and J. J. O’Shea, “TGF-Beta Does Not Inhibit IL-12- and IL-2-Induced Activation of Janus Kinases and STATs,” Journal of Immunology, Vol. 162, No. 5, 1999, pp. 2974-2981.
[6] R. A. Seder and W. E. Paul, “Acquisition of Lymphokine-Producing Phenotype by CD4+ T Cells,” Annual Review of Immunology, Vol. 12, 1994, pp. 635-673. doi:10.1146/annurev.iy.12.040194.003223
[7] G. Trinchieri, “Interleukin-12 and the Regulation of Innate Resistance and Adaptive Immunity,” Nature Reviews Immunology, Vol. 3, No. 2, 2003, pp. 133-146. doi:10.1038/nri1001
[8] N. G. Jacobson, S. J. Szabo, R. M. Weber-Nordt, Z. Zhong, R. D. Schreiber, J. E. Darnell Jr. and K. M. Murphy, “Interleukin 12 Signaling in T Helper Type 1 (Th1) Cells Involves Tyrosine Phosphorylation of Signal Transducer and Activator of Transcription (Stat)3 and Stat4,” Journal of Experimental Medicine, Vol. 181, No. 5, 1995, pp. 1755-1762. doi:10.1084/jem.181.5.1755
[9] F. Nimmerjahn and J. V. Ravetch, “Divergent Immunoglobulin g Subclass Activity through Selective Fc Receptor Binding,” Science, Vol. 310, No. 5753, 2005, pp. 1510-1512. doi:10.1126/science.1118948
[10] R. Parihar, P. Nadella, A. Lewis, R. Jensen, C. De Hoff, J. E. Dierksheide, A. M. VanBuskirk, C. M. Magro, D. C. Young, C. L. Shapiro and W. E. Carson III, “A Phase I Study of Interleukin 12 with Trastuzumab in Patients with Human Epidermal Growth Factor Receptor-2-Overexpressing Malignancies: Analysis of Sustained Interferon Gamma Production in a Subset of Patients,” Clinical Cancer Research, Vol. 10, No. 15, 2004, pp. 5027-5037. doi:10.1158/1078-0432.CCR-04-0265
[11] P. Bonomi, K. Kim, D. Fairclough, D. Cella, J. Kugler, E. Rowinsky, M. Jiroutek and D. Johnson, “Comparison of Survival and Quality of Life in Advanced Non-Small-Cell Lung Cancer Patients Treated with Two Dose Levels of Paclitaxel Combined with Cisplatin versus Etoposide with Cisplatin: Results of an Eastern Cooperative Oncology Group Trial,” Journal of Clinical Oncology, Vol. 18, No. 3, 2000, pp. 623-631.
[12] I. Airoldi, E. Di Carlo, C. Cocco, E. Caci, M. Cilli, C. Sorrentino, G. Sozzi, S. Ferrini, S. Rosini, G. Bertolini, M. Truini, F. Grossi, L. J. Galietta, D. Ribatti and V. Pistoia, “IL-12 Can Target Human Lung Adenocarcinoma Cells and Normal Bronchial Epithelial Cells Surrounding Tumor Lesions,” PLoS One, Vol. 4, No. 7, 2009, Article ID: e6119. doi:10.1371/journal.pone.0006119
[13] C. Halin, S. Rondini, F. Nilsson, A. Berndt, H. Kosmehl, L. Zardi and D. Neri, “Enhancement of the Antitumor Activity of Interleukin-12 by Targeted Delivery to Neovasculature,” Nature Biotechnology, Vol. 20, No. 3, 2002, pp. 264-269. doi:10.1038/nbt0302-264
[14] M. P. Colombo and G. Trinchieri, “Interleukin-12 in Anti-Tumor Immunity and Immunotherapy,” Cytokine & Growth Factor Reviews, Vol. 13, No. 2, 2002, pp. 155-168. doi:10.1016/S1359-6101(01)00032-6
[15] J. P. Leonard, M. L. Sherman, G. L. Fisher, L. J. Buchanan, G. Larsen, M. B. Atkins, J. A. Sosman, J. P. Dutcher, N. J. Vogelzang and J. L. Ryan, “Effects of Single-Dose Interleukin-12 Exposure on Interleukin-12-Associated Toxicity and Interferon-Gamma Production,” Blood, Vol. 90, No. 7, 1997, pp. 2541-2548.
[16] J. A. Gollob, K. G. Veenstra, R. A. Parker, J. W. Mier, D. F. McDermott, D. Clancy, L. Tutin, H. Koon and M. B. Atkins, “Phase I Trial of Concurrent Twice-Weekly Recombinant Human Interleukin-12 Plus Low-Dose IL-2 in Patients with Melanoma or Renal Cell Carcinoma,” Journal of Clinical Oncology, Vol. 21, No. 13, 2003, pp. 2564-2573. doi:10.1200/JCO.2003.12.119
[17] H. Ren, T. Boulikas, K. Lundstrom, A. Soling, P. C. Warnke and N. G. Rainov, “Immunogene Therapy of Recurrent Glioblastoma Multiforme with a Liposomally Encapsulated Replication-Incompetent Semliki Forest Virus Vector Carrying the Human Interleukin-12 Gene—A Phase I/II Clinical Protocol,” Journal of Neuro-Oncology, Vol. 64, No. 1-2, 2003, pp. 147-154. doi:10.1007/BF02700029
[18] L. Heinzerling, G. Burg, R. Dummer, T. Maier, P. A. Oberholzer, J. Schultz, L. Elzaouk, J. Pavlovic and K. Moelling, “Intratumoral Injection of DNA Encoding Human Interleukin 12 into Patients with Metastatic Melanoma: Clinical Efficacy,” Human Gene Therapy, Vol. 16, No. 1, 2005, pp. 35-48. doi:10.1089/hum.2005.16.35
[19] D. M. Mahvi, M. B. Henry, M. R. Albertini, S. Weber, K. Meredith, H. Schalch, A. Rakhmilevich, J. Hank and P. Sondel, “Intratumoral Injection of IL-12 Plasmid DNA—Results of a Phase I/IB Clinical Trial,” Cancer Gene Therapy, Vol. 14, No. 8, 2007, pp. 717-723. doi:10.1038/sj.cgt.7701064
[20] S. Gariboldi, M. Palazzo, L. Zanobbio, G. F. Dusio, V. Mauro, U. Solimene, D. Cardani, M. Mantovani and C. Rumio, “Low Dose Oral Administration of Cytokines for Treatment of Allergic Asthma,” Pulmonary Pharmacology & Therapeutics, Vol. 22, No. 6, 2009, pp. 497-510. doi:10.1016/j.pupt.2009.05.002
[21] I. Jedema, N. M. van der Werff, R. M. Barge, R. Willemze and J. H. Falkenburg, “New CFSE-Based Assay to Determine Susceptibility to Lysis by Cytotoxic T Cells of Leukemic Precursor Cells within a Heterogeneous Target Cell Population,” Blood, Vol. 103, No. 7, 2004, pp. 2677-2682.
[22] R. J. Soiffer, M. J. Robertson, C. Murray, K. Cochran and J. Ritz, “Interleukin-12 Augments Cytolytic Activity of Peripheral Blood Lymphocytes from Patients with Hematologic and Solid Malignancies,” Blood, Vol. 82, No. 9, 1993, pp. 2790-2796.
[23] A. R. Rossi, F. Pericle, S. Rashleigh, J. Janiec and J. Y. Djeu, “Lysis of Neuroblastoma Cell Lines by Human Natural Killer Cells Activated by Interleukin-2 and Interleukin-12,” Blood, Vol. 83, No. 5, 1994, pp. 1323-1328.
[24] D. J. Campbell and M. A. Koch, “Phenotypical and Functional Specialization of FOXP3+ Regulatory T Cells,” Nature Reviews Immunology, Vol. 11, No. 2, 2011, pp. 119-130.

comments powered by Disqus

Copyright © 2020 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.