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 language | English (US) |
|---|---|
| Pages (from-to) | 941-946 |
| Number of pages | 6 |
| Journal | Journal of Pediatric Surgery |
| Volume | 39 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2004 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Restored immune response to an MHC-II-restricted antigen in tumor-bearing hosts after elimination of regulatory T cells
AU - Nicholl, Michael
AU - Lodge, Andrew
AU - Brown, Ian Elliott
AU - Sugg, Sonia L.
AU - Shilyansky, Joel
PY - 2004/6
Y1 - 2004/6
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.
KW - Cancer
KW - CD25
KW - immunotherapy
KW - T cell
KW - tolerance
UR - http://www.scopus.com/inward/record.url?scp=3042667799&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=3042667799&partnerID=8YFLogxK
U2 - 10.1016/j.jpedsurg.2004.02.049
DO - 10.1016/j.jpedsurg.2004.02.049
M3 - Article
C2 - 15185230
AN - SCOPUS:3042667799
VL - 39
SP - 941
EP - 946
JO - Journal of Pediatric Surgery
JF - Journal of Pediatric Surgery
SN - 0022-3468
IS - 6
ER -