Restored immune response to an MHC-II-restricted antigen in tumor-bearing hosts after elimination of regulatory T cells

Michael Nicholl, Andrew Lodge, Ian Elliott Brown, Sonia L. Sugg, Joel Shilyansky

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background/purpose Pediatric sarcomas have a poor prognosis, recur frequently, and are not effectively treated by currently available therapy. Immunotherapy is a promising treatment modality; however, to be successful, immune tolerance must be overcome. CD4+CD25+ T cells are immunosuppressive. The authors hypothesize that immune tolerance may be overcome by eliminating the regulatory CD4+CD25+ T cells, which are induced by tumor. Methods A murine fibrosarcoma (MF), which expresses an MHC-II-restricted tumor antigen (mL26), was injected subcutaneously. CD4 + T cells were isolated and CD25+ population examined. Monoclonal antibody was used to deplete CD25+ T cells. Proliferation to mL26 was used to determine CD4+ T cell response to tumor-associated antigen (TAA). Results Depletion of CD25+ cells prevented tumor establishment. Tumor-infiltrating CD25+ T cells, which madeup 48% of CD4+ T cells in tumors, suppressed proliferation in allogeneic mixed lymphocyte reactions. Draining lymph node cells from tumor-bearing (TB) mice did not proliferate in response to mL26, whereas those from naive mice responded vigorously. Depletion of CD25+ cells before immunization restored response to mL26 in TB mice. Conclusions CD4 +CD25+ T cells induced by MF facilitate tumor establishment and maintain immune tolerance. Depletion of CD4 +CD25+ T cells may be an effective means for reversing tumor tolerance and enhancing cancer vaccines.

Original languageEnglish (US)
Pages (from-to)941-946
Number of pages6
JournalJournal of Pediatric Surgery
Volume39
Issue number6
DOIs
StatePublished - Jun 2004
Externally publishedYes

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Neoplasm Antigens
Regulatory T-Lymphocytes
T-Lymphocytes
Immune Tolerance
Neoplasms
Fibrosarcoma
Mixed Lymphocyte Culture Test
Cancer Vaccines
Immunosuppressive Agents
Sarcoma
Immunotherapy
Immunization
Lymph Nodes
Monoclonal Antibodies
Pediatrics
Therapeutics

Keywords

  • Cancer
  • CD25
  • immunotherapy
  • T cell
  • tolerance

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Surgery

Cite this

Restored immune response to an MHC-II-restricted antigen in tumor-bearing hosts after elimination of regulatory T cells. / Nicholl, Michael; Lodge, Andrew; Brown, Ian Elliott; Sugg, Sonia L.; Shilyansky, Joel.

In: Journal of Pediatric Surgery, Vol. 39, No. 6, 06.2004, p. 941-946.

Research output: Contribution to journalArticle

Nicholl, Michael ; Lodge, Andrew ; Brown, Ian Elliott ; Sugg, Sonia L. ; Shilyansky, Joel. / Restored immune response to an MHC-II-restricted antigen in tumor-bearing hosts after elimination of regulatory T cells. In: Journal of Pediatric Surgery. 2004 ; Vol. 39, No. 6. pp. 941-946.
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abstract = "Background/purpose Pediatric sarcomas have a poor prognosis, recur frequently, and are not effectively treated by currently available therapy. Immunotherapy is a promising treatment modality; however, to be successful, immune tolerance must be overcome. CD4+CD25+ T cells are immunosuppressive. The authors hypothesize that immune tolerance may be overcome by eliminating the regulatory CD4+CD25+ T cells, which are induced by tumor. Methods A murine fibrosarcoma (MF), which expresses an MHC-II-restricted tumor antigen (mL26), was injected subcutaneously. CD4 + T cells were isolated and CD25+ population examined. Monoclonal antibody was used to deplete CD25+ T cells. Proliferation to mL26 was used to determine CD4+ T cell response to tumor-associated antigen (TAA). Results Depletion of CD25+ cells prevented tumor establishment. Tumor-infiltrating CD25+ T cells, which madeup 48{\%} of CD4+ T cells in tumors, suppressed proliferation in allogeneic mixed lymphocyte reactions. Draining lymph node cells from tumor-bearing (TB) mice did not proliferate in response to mL26, whereas those from naive mice responded vigorously. Depletion of CD25+ cells before immunization restored response to mL26 in TB mice. Conclusions CD4 +CD25+ T cells induced by MF facilitate tumor establishment and maintain immune tolerance. Depletion of CD4 +CD25+ T cells may be an effective means for reversing tumor tolerance and enhancing cancer vaccines.",
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N2 - Background/purpose Pediatric sarcomas have a poor prognosis, recur frequently, and are not effectively treated by currently available therapy. Immunotherapy is a promising treatment modality; however, to be successful, immune tolerance must be overcome. CD4+CD25+ T cells are immunosuppressive. The authors hypothesize that immune tolerance may be overcome by eliminating the regulatory CD4+CD25+ T cells, which are induced by tumor. Methods A murine fibrosarcoma (MF), which expresses an MHC-II-restricted tumor antigen (mL26), was injected subcutaneously. CD4 + T cells were isolated and CD25+ population examined. Monoclonal antibody was used to deplete CD25+ T cells. Proliferation to mL26 was used to determine CD4+ T cell response to tumor-associated antigen (TAA). Results Depletion of CD25+ cells prevented tumor establishment. Tumor-infiltrating CD25+ T cells, which madeup 48% of CD4+ T cells in tumors, suppressed proliferation in allogeneic mixed lymphocyte reactions. Draining lymph node cells from tumor-bearing (TB) mice did not proliferate in response to mL26, whereas those from naive mice responded vigorously. Depletion of CD25+ cells before immunization restored response to mL26 in TB mice. Conclusions CD4 +CD25+ T cells induced by MF facilitate tumor establishment and maintain immune tolerance. Depletion of CD4 +CD25+ T cells may be an effective means for reversing tumor tolerance and enhancing cancer vaccines.

AB - Background/purpose Pediatric sarcomas have a poor prognosis, recur frequently, and are not effectively treated by currently available therapy. Immunotherapy is a promising treatment modality; however, to be successful, immune tolerance must be overcome. CD4+CD25+ T cells are immunosuppressive. The authors hypothesize that immune tolerance may be overcome by eliminating the regulatory CD4+CD25+ T cells, which are induced by tumor. Methods A murine fibrosarcoma (MF), which expresses an MHC-II-restricted tumor antigen (mL26), was injected subcutaneously. CD4 + T cells were isolated and CD25+ population examined. Monoclonal antibody was used to deplete CD25+ T cells. Proliferation to mL26 was used to determine CD4+ T cell response to tumor-associated antigen (TAA). Results Depletion of CD25+ cells prevented tumor establishment. Tumor-infiltrating CD25+ T cells, which madeup 48% of CD4+ T cells in tumors, suppressed proliferation in allogeneic mixed lymphocyte reactions. Draining lymph node cells from tumor-bearing (TB) mice did not proliferate in response to mL26, whereas those from naive mice responded vigorously. Depletion of CD25+ cells before immunization restored response to mL26 in TB mice. Conclusions CD4 +CD25+ T cells induced by MF facilitate tumor establishment and maintain immune tolerance. Depletion of CD4 +CD25+ T cells may be an effective means for reversing tumor tolerance and enhancing cancer vaccines.

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