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Nitric Oxide Regulation during Anti-tumor Immunotherapy

Badn, Wiaam LU (2007)
Abstract
During tumor progression a strong immunosuppression is developed and is believed to be the major reason why immunotherapy fails. This suppression is induced in response to factors produced from tumor cells, but can also be induced after immunotherapy. NO has been shown to play a major role in this suppression both in patients with gliomas and colon carcinomas. The aim of this thesis is to clarify the role of the NO mediated immunosuppression in rats with intra-hepatic colon carcinomas and intra-cerebral gliomas, and to clarify whether inhibition of NO inducing enzyme, iNOS, would diminish this suppression and improve the anti-tumor immunotherapy.



In study I-IV we investigated both unspecific and specific iNOS inhibitors,... (More)
During tumor progression a strong immunosuppression is developed and is believed to be the major reason why immunotherapy fails. This suppression is induced in response to factors produced from tumor cells, but can also be induced after immunotherapy. NO has been shown to play a major role in this suppression both in patients with gliomas and colon carcinomas. The aim of this thesis is to clarify the role of the NO mediated immunosuppression in rats with intra-hepatic colon carcinomas and intra-cerebral gliomas, and to clarify whether inhibition of NO inducing enzyme, iNOS, would diminish this suppression and improve the anti-tumor immunotherapy.



In study I-IV we investigated both unspecific and specific iNOS inhibitors, and we could show that the specific iNOS inhibitors were superior in enhancing immune responses, including lymphocyte proliferation and cytokine production, as well as nitrite reduction. The specific iNOS inhibitor mercaptoethylguanidine, MEG, was the most effective inhibitor. MEG in combination with IFN-? based immunotherapy prolonged the survival and increased the cure rate three fold of rats with intra-cerebral gliomas. Interestingly, the inhibition of NO by MEG was time dependent, and the prolonged survival was achieved only when MEG was administered after more than one immunization. The prolonged survival seemed to be dependent on enhanced local and systemic immune responses. MEG treatment significantly increased the lymphocyte numbers both in the spleen and in the tumor draining lymph nodes (the deep cervical lymph nodes). In the deep cervical lymph nodes, MEG treatment increased CD4+ T cells but not the B cells, suggesting a skewing toward a Th1 immunity, which is important during tumor eradication. Furthermore, MEG treatment decreased the auto-reactive and the suppressive CD8+CD25+ T cells. In the colon carcinoma model, we showed that additional suppressive mechanism exists, which is mediated by the enzyme cyclooxygenase (COX). The inhibition of both NOS and COX increased immune responses six times as compared to inhibition of each enzyme alone. Finally, treatment with MEG in combination IL-18/IFN-? reduced tumor volume by 50 % in rats with colon carcinomas. MEG has been shown to inhibit production of both iNOS and COX, which might explain its superior effects compared to the other NOS inhibitors. Thus we have been able to show that immunotherapy using tumor cells genetically modified to produce cytokines could be used to eradicate established tumors, however, only when combined with therapies that minimize the immune suppression developed during tumor progression. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

Tumörer kan på olika sätt hämma immunsystemet och detta kan vara orsaken till varför immunterapi mot tumörer oftast inte lyckas. Denna nedreglering av immunförsvaret kan medieras av faktorer producerade från tumörcellerna själva eller så kan den följa efter en stark immunstimulering som satts igång av immunterapi. Kväve monoxid (NO) har visats vara en av de ämnen som kan mediera detta, både hos patienter med tjocktarmcancer och patienter med hjärntumörer. Målet med denna avhandling var att klargöra rollen av NO medierad immunhämning i två råttmodeller, en med lever metastas av tjortarmscancer och en intra-cerebral hjärntumör modell. Samtidigt ville vi undersöka om hämningen av det NO inducerande... (More)
Popular Abstract in Swedish

Tumörer kan på olika sätt hämma immunsystemet och detta kan vara orsaken till varför immunterapi mot tumörer oftast inte lyckas. Denna nedreglering av immunförsvaret kan medieras av faktorer producerade från tumörcellerna själva eller så kan den följa efter en stark immunstimulering som satts igång av immunterapi. Kväve monoxid (NO) har visats vara en av de ämnen som kan mediera detta, både hos patienter med tjocktarmcancer och patienter med hjärntumörer. Målet med denna avhandling var att klargöra rollen av NO medierad immunhämning i två råttmodeller, en med lever metastas av tjortarmscancer och en intra-cerebral hjärntumör modell. Samtidigt ville vi undersöka om hämningen av det NO inducerande enzymet (iNOS) skulle kunna motverka immunhämningen och därmed kunna förbättra anti-tumör immunterapier. I studie I-IV undersökte vi både ospecifika och specifika iNOS hämmare i kombination med immunterapi, och vi visade att dem specifika iNOS hämmaren var bättre på att förstärka olika immunreaktioner. Den specifika hämmaren MEG var mest effektiv. MEG behandling i kombination med cykokin (IFN-?) baserad immunterapi resulterade i förlängd överlevnad och ökade botfrekvensen tre gånger i råttmodellen med intra-cerebral hjärntumör. Inhibitionen av NO med MEG var tidsberoende, och den förlängda överlevnaden uppnådes endast när MEG administrerades efter mer än en immuniseringsomgång. Effekten av MEG verkade bero på aktivering av både det lokala och systemiska immunförsvaret. Behandlingen med MEG ökade lymfocyt antalet både i mjälte och i dränerande lymfkörtlar (de djupa cervikala lymfkörtlarna). I de djupa cervikala lymfkörtlarna, ökade MEG behandlingen antalet CD4+ T celler men påverkade inte antalet B celler. Dessutom, så reducerade MEG de auto-reaktiva och hämmande CD8+CD25+ T cellerna. I tjocktarmscancer modellen visade vi att även en annan supprimerande molekyl, prostaglandin E2 spelar roll, vilket induceras av enzymet cyklooxygenas (COX). Samtidig inhibition av NOS och COX resulterade i förstärkta immunreaktioner, upp till sex gånger större jämfört med hämning av var enzym för sig. MEG i kombination IL-18/IFN-? immunisering reducerade tumörvolymen upp till 50 % i råttor med tjocktarmscancer. MEG har i tidagare studier visats att hämma både iNOS och COX, vilket kan förklara dess överlägsna effekt jämfört med andra NOS hämmare. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Bronte, Vincenzo, Department of Oncologickal and Surgical Sciences
organization
publishing date
type
Thesis
publication status
published
subject
keywords
transplantation, Immunologi, serology, Immunology, Medicin (människa och djur), immunotherapy, Medicine (human and vertebrates), immunosuppression, PGE2, Nitric oxide, serologi
pages
140 pages
publisher
Department of Neurosurgery, Clinical Sciences, Lund University
defense location
Segerfalks salen, BMC, hus A
defense date
2007-04-20 13:00:00
ISBN
978-91-85559-36-7
1652-8220
language
English
LU publication?
yes
additional info
Wiaam Badn, Suzanne Kalliomäki, Bengt Widegren and Hans Olov Sjögren. 2006. Low-Dose Combretastatin A4 Phosphate Enhances the Immune Response of Tumor Hosts to Experimental Colon Carcinoma. Clin Cancer Res., vol 1:12 pp 4714-9.
Wiaam Badn, Pontus Hegardt, Maria A Fellert, Anna Darabi, Magnus Esbjörnsson, Karin Enell Smith, Shorena Janelidze, Leif G Salford, Edward Visse and Peter Siesjö. 2007. Inhibition of inducible nitric oxide synthase enhances anti-tumor immune responses in rats immunized with IFN-? secreting glioma cells. Scand J Immunol, vol 65 pp 289-97.
Wiaam Badn, Edward Visse, Anna Darabi, Karin Enell Smith, Leif G Salford and Peter Siesjö. . Post-immunization with IFN-? secreting glioma cells combined with the iNOS inhibitor mercaptoethylguanidine (MEG) prolongs survival of rats with intracerebral tumors. Journal of Immunology, (submitted)
Wiaam Badn, Hans Olov Sjögren and Peter Siesjö. . Nitric oxide and Prostaglandin-2 inhibition by Mercaptoethylguanidine (MEG) enhances the immune response and decreases the tumor burden of post-immunized rats with Colon Carcinoma. (manuscript)
id
5c541c1f-6a8e-46ef-bdbc-5b5af05ecbc7 (old id 548342)
date added to LUP
2016-04-04 10:53:55
date last changed
2018-11-21 21:01:26
@phdthesis{5c541c1f-6a8e-46ef-bdbc-5b5af05ecbc7,
  abstract     = {{During tumor progression a strong immunosuppression is developed and is believed to be the major reason why immunotherapy fails. This suppression is induced in response to factors produced from tumor cells, but can also be induced after immunotherapy. NO has been shown to play a major role in this suppression both in patients with gliomas and colon carcinomas. The aim of this thesis is to clarify the role of the NO mediated immunosuppression in rats with intra-hepatic colon carcinomas and intra-cerebral gliomas, and to clarify whether inhibition of NO inducing enzyme, iNOS, would diminish this suppression and improve the anti-tumor immunotherapy.<br/><br>
<br/><br>
In study I-IV we investigated both unspecific and specific iNOS inhibitors, and we could show that the specific iNOS inhibitors were superior in enhancing immune responses, including lymphocyte proliferation and cytokine production, as well as nitrite reduction. The specific iNOS inhibitor mercaptoethylguanidine, MEG, was the most effective inhibitor. MEG in combination with IFN-? based immunotherapy prolonged the survival and increased the cure rate three fold of rats with intra-cerebral gliomas. Interestingly, the inhibition of NO by MEG was time dependent, and the prolonged survival was achieved only when MEG was administered after more than one immunization. The prolonged survival seemed to be dependent on enhanced local and systemic immune responses. MEG treatment significantly increased the lymphocyte numbers both in the spleen and in the tumor draining lymph nodes (the deep cervical lymph nodes). In the deep cervical lymph nodes, MEG treatment increased CD4+ T cells but not the B cells, suggesting a skewing toward a Th1 immunity, which is important during tumor eradication. Furthermore, MEG treatment decreased the auto-reactive and the suppressive CD8+CD25+ T cells. In the colon carcinoma model, we showed that additional suppressive mechanism exists, which is mediated by the enzyme cyclooxygenase (COX). The inhibition of both NOS and COX increased immune responses six times as compared to inhibition of each enzyme alone. Finally, treatment with MEG in combination IL-18/IFN-? reduced tumor volume by 50 % in rats with colon carcinomas. MEG has been shown to inhibit production of both iNOS and COX, which might explain its superior effects compared to the other NOS inhibitors. Thus we have been able to show that immunotherapy using tumor cells genetically modified to produce cytokines could be used to eradicate established tumors, however, only when combined with therapies that minimize the immune suppression developed during tumor progression.}},
  author       = {{Badn, Wiaam}},
  isbn         = {{978-91-85559-36-7}},
  keywords     = {{transplantation; Immunologi; serology; Immunology; Medicin (människa och djur); immunotherapy; Medicine (human and vertebrates); immunosuppression; PGE2; Nitric oxide; serologi}},
  language     = {{eng}},
  publisher    = {{Department of Neurosurgery, Clinical Sciences, Lund University}},
  school       = {{Lund University}},
  title        = {{Nitric Oxide Regulation during Anti-tumor Immunotherapy}},
  year         = {{2007}},
}