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

J Pediatr Surg. 2004 Jun;39(6):941-6; discussion 941-6. doi: 10.1016/j.jpedsurg.2004.02.049.

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 made up 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.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • Female
  • Fibrosarcoma / immunology*
  • Fibrosarcoma / therapy
  • Flow Cytometry
  • Histocompatibility Antigens Class II / immunology*
  • Immune Tolerance
  • Immunization
  • Immunotherapy
  • Lymph Nodes / immunology
  • Lymph Nodes / pathology
  • Lymphocyte Activation
  • Lymphocyte Culture Test, Mixed
  • Lymphocyte Depletion*
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Mice
  • Mice, Inbred C3H
  • Molecular Sequence Data
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / immunology
  • Neoplasm Transplantation
  • Neoplasms, Radiation-Induced / immunology
  • Neoplasms, Radiation-Induced / therapy
  • Receptors, Interleukin-2 / analysis
  • Ribosomal Proteins / genetics
  • Ribosomal Proteins / immunology
  • Specific Pathogen-Free Organisms
  • T-Lymphocyte Subsets / immunology*

Substances

  • Antigens, Neoplasm
  • Histocompatibility Antigens Class II
  • Neoplasm Proteins
  • Receptors, Interleukin-2
  • Ribosomal Proteins
  • Rpl26 protein, mouse