Restored immune response to an MHC-II-Restricted antigen in tumor-bearing hosts after elimination of regulatory T cells.
OBJECTIVE
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.
Nicholl
Michael
M
Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA.
Lodge
Andrew
A
Brown
Ian
I
Sugg
Sonia L
SL
Shilyansky
Joel
J
D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology* / Q000628:therapy; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D007108:Immune Tolerance; D007114:Immunization; D007167:Immunotherapy; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008212:Lymphocyte Depletion; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology; D009368:Neoplasm Transplantation; D009381:Neoplasms, Radiation-Induced / Q000276:immunology / Q000628:therapy; D015375:Receptors, Interleukin-2 / Q000032:analysis; D012269:Ribosomal Proteins / Q000235:genetics / Q000276:immunology; D013047:Specific Pathogen-Free Organisms; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D000951:Antigens, Neoplasm; D000949:Histocompatibility Antigens Class II; D009363:Neoplasm Proteins; D015375:Receptors, Interleukin-2; D012269:Ribosomal Proteins; C060480:Rpl26 protein, mouse