Murine rhabdomyosarcoma is immunogenic and responsive to T-cell-based immunotherapy

Joanna L. Meadors, Yonghzi Cui, Qing Rong Chen, Young K. Song, Javed Khan, Glenn Merlino, Maria Tsokos, Rimas J. Orentas, Crystal L. Mackall

Research output: Contribution to journalArticle

Abstract

Background: Immunotherapies targeting cellular immunity are currently approved for treatment of melanoma, renal cell carcinoma, and prostate cancer. Studies on the immunogenicity and immune responsiveness of pediatric tumors are limited, therefore, it remains unclear to what extent T-cell-based immunotherapy holds promise for pediatric solid tumors. Procedure: A new rhabdomyosarcoma cell line (M3-9-M) was derived from an embryonal rhabdomyosarcoma (ERMS) occurring in a C57BL/6 mouse transgenic for hepatocyte growth factor and heterozygous for mutated p53. Primary tumors and metastases derived from M3-9-M were studied for similarities to human ERMS, and for immunogenicity and immune responsiveness. Results: Primary and metastatic tumors develop after orthotopic injection of M3-9-M into immunocompetent C57BL/6 mice, which mirror human ERMS with regard to histology, gene expression, and metastatic behavior. Whole cell vaccination using irradiated M3-9-M cells or M3-9-M-pulsed dendritic cells (DC)-induced tumor-specific T-cell responses that prevent tumor growth following low-dose tumor injection, and slow tumor growth following higher doses. Administration of anti-CD25 moAbs to deplete CD4 +CD25 +FOXP3 + regulatory T cells prior to tumor vaccination enhanced the potency of the ERMS tumor vaccine. Adoptive immunotherapy with M3-9-M primed T cells plus DC-based vaccination resulted in complete eradication of day 10 M3-9-M derived tumors. Conclusions: M3-9-M derived murine ERMS is immunogenic and immunoresponsive; regulatory T cells contribute to immune evasion by murine rhabdomyosarcoma. Adoptive immunotherapy with DC vaccination can eradicate low tumor burdens. Future work will seek to identify the tumor-associated antigens that mediate protective and therapeutic immunity in this model.

Original languageEnglish (US)
Pages (from-to)921-929
Number of pages9
JournalPediatric Blood and Cancer
Volume57
Issue number6
DOIs
StatePublished - Dec 1 2011
Externally publishedYes

Fingerprint

Rhabdomyosarcoma
Immunotherapy
Embryonal Rhabdomyosarcoma
T-Lymphocytes
Neoplasms
Vaccination
Dendritic Cells
Adoptive Immunotherapy
Regulatory T-Lymphocytes
Inbred C57BL Mouse
Renal Cell Carcinoma
Pediatrics
Immune Evasion
Cancer Vaccines
Injections
Neoplasm Antigens
Growth
Tumor Burden
Cellular Immunity
Immunity

Keywords

  • Adoptive immunotherapy
  • Embryonal rhabdomyosarcoma
  • Immunotherapy
  • Regulatory T cells
  • Rhabdomyosarcoma
  • Tumor antigen
  • Tumor vaccine

ASJC Scopus subject areas

  • Oncology
  • Pediatrics, Perinatology, and Child Health
  • Hematology

Cite this

Meadors, J. L., Cui, Y., Chen, Q. R., Song, Y. K., Khan, J., Merlino, G., ... Mackall, C. L. (2011). Murine rhabdomyosarcoma is immunogenic and responsive to T-cell-based immunotherapy. Pediatric Blood and Cancer, 57(6), 921-929. https://doi.org/10.1002/pbc.23048

Murine rhabdomyosarcoma is immunogenic and responsive to T-cell-based immunotherapy. / Meadors, Joanna L.; Cui, Yonghzi; Chen, Qing Rong; Song, Young K.; Khan, Javed; Merlino, Glenn; Tsokos, Maria; Orentas, Rimas J.; Mackall, Crystal L.

In: Pediatric Blood and Cancer, Vol. 57, No. 6, 01.12.2011, p. 921-929.

Research output: Contribution to journalArticle

Meadors, JL, Cui, Y, Chen, QR, Song, YK, Khan, J, Merlino, G, Tsokos, M, Orentas, RJ & Mackall, CL 2011, 'Murine rhabdomyosarcoma is immunogenic and responsive to T-cell-based immunotherapy', Pediatric Blood and Cancer, vol. 57, no. 6, pp. 921-929. https://doi.org/10.1002/pbc.23048
Meadors, Joanna L. ; Cui, Yonghzi ; Chen, Qing Rong ; Song, Young K. ; Khan, Javed ; Merlino, Glenn ; Tsokos, Maria ; Orentas, Rimas J. ; Mackall, Crystal L. / Murine rhabdomyosarcoma is immunogenic and responsive to T-cell-based immunotherapy. In: Pediatric Blood and Cancer. 2011 ; Vol. 57, No. 6. pp. 921-929.
@article{d0d00fe4a242445dab1f96493391082a,
title = "Murine rhabdomyosarcoma is immunogenic and responsive to T-cell-based immunotherapy",
abstract = "Background: Immunotherapies targeting cellular immunity are currently approved for treatment of melanoma, renal cell carcinoma, and prostate cancer. Studies on the immunogenicity and immune responsiveness of pediatric tumors are limited, therefore, it remains unclear to what extent T-cell-based immunotherapy holds promise for pediatric solid tumors. Procedure: A new rhabdomyosarcoma cell line (M3-9-M) was derived from an embryonal rhabdomyosarcoma (ERMS) occurring in a C57BL/6 mouse transgenic for hepatocyte growth factor and heterozygous for mutated p53. Primary tumors and metastases derived from M3-9-M were studied for similarities to human ERMS, and for immunogenicity and immune responsiveness. Results: Primary and metastatic tumors develop after orthotopic injection of M3-9-M into immunocompetent C57BL/6 mice, which mirror human ERMS with regard to histology, gene expression, and metastatic behavior. Whole cell vaccination using irradiated M3-9-M cells or M3-9-M-pulsed dendritic cells (DC)-induced tumor-specific T-cell responses that prevent tumor growth following low-dose tumor injection, and slow tumor growth following higher doses. Administration of anti-CD25 moAbs to deplete CD4 +CD25 +FOXP3 + regulatory T cells prior to tumor vaccination enhanced the potency of the ERMS tumor vaccine. Adoptive immunotherapy with M3-9-M primed T cells plus DC-based vaccination resulted in complete eradication of day 10 M3-9-M derived tumors. Conclusions: M3-9-M derived murine ERMS is immunogenic and immunoresponsive; regulatory T cells contribute to immune evasion by murine rhabdomyosarcoma. Adoptive immunotherapy with DC vaccination can eradicate low tumor burdens. Future work will seek to identify the tumor-associated antigens that mediate protective and therapeutic immunity in this model.",
keywords = "Adoptive immunotherapy, Embryonal rhabdomyosarcoma, Immunotherapy, Regulatory T cells, Rhabdomyosarcoma, Tumor antigen, Tumor vaccine",
author = "Meadors, {Joanna L.} and Yonghzi Cui and Chen, {Qing Rong} and Song, {Young K.} and Javed Khan and Glenn Merlino and Maria Tsokos and Orentas, {Rimas J.} and Mackall, {Crystal L.}",
year = "2011",
month = "12",
day = "1",
doi = "10.1002/pbc.23048",
language = "English (US)",
volume = "57",
pages = "921--929",
journal = "Pediatric Blood and Cancer",
issn = "1545-5009",
publisher = "Wiley-Liss Inc.",
number = "6",

}

TY - JOUR

T1 - Murine rhabdomyosarcoma is immunogenic and responsive to T-cell-based immunotherapy

AU - Meadors, Joanna L.

AU - Cui, Yonghzi

AU - Chen, Qing Rong

AU - Song, Young K.

AU - Khan, Javed

AU - Merlino, Glenn

AU - Tsokos, Maria

AU - Orentas, Rimas J.

AU - Mackall, Crystal L.

PY - 2011/12/1

Y1 - 2011/12/1

N2 - Background: Immunotherapies targeting cellular immunity are currently approved for treatment of melanoma, renal cell carcinoma, and prostate cancer. Studies on the immunogenicity and immune responsiveness of pediatric tumors are limited, therefore, it remains unclear to what extent T-cell-based immunotherapy holds promise for pediatric solid tumors. Procedure: A new rhabdomyosarcoma cell line (M3-9-M) was derived from an embryonal rhabdomyosarcoma (ERMS) occurring in a C57BL/6 mouse transgenic for hepatocyte growth factor and heterozygous for mutated p53. Primary tumors and metastases derived from M3-9-M were studied for similarities to human ERMS, and for immunogenicity and immune responsiveness. Results: Primary and metastatic tumors develop after orthotopic injection of M3-9-M into immunocompetent C57BL/6 mice, which mirror human ERMS with regard to histology, gene expression, and metastatic behavior. Whole cell vaccination using irradiated M3-9-M cells or M3-9-M-pulsed dendritic cells (DC)-induced tumor-specific T-cell responses that prevent tumor growth following low-dose tumor injection, and slow tumor growth following higher doses. Administration of anti-CD25 moAbs to deplete CD4 +CD25 +FOXP3 + regulatory T cells prior to tumor vaccination enhanced the potency of the ERMS tumor vaccine. Adoptive immunotherapy with M3-9-M primed T cells plus DC-based vaccination resulted in complete eradication of day 10 M3-9-M derived tumors. Conclusions: M3-9-M derived murine ERMS is immunogenic and immunoresponsive; regulatory T cells contribute to immune evasion by murine rhabdomyosarcoma. Adoptive immunotherapy with DC vaccination can eradicate low tumor burdens. Future work will seek to identify the tumor-associated antigens that mediate protective and therapeutic immunity in this model.

AB - Background: Immunotherapies targeting cellular immunity are currently approved for treatment of melanoma, renal cell carcinoma, and prostate cancer. Studies on the immunogenicity and immune responsiveness of pediatric tumors are limited, therefore, it remains unclear to what extent T-cell-based immunotherapy holds promise for pediatric solid tumors. Procedure: A new rhabdomyosarcoma cell line (M3-9-M) was derived from an embryonal rhabdomyosarcoma (ERMS) occurring in a C57BL/6 mouse transgenic for hepatocyte growth factor and heterozygous for mutated p53. Primary tumors and metastases derived from M3-9-M were studied for similarities to human ERMS, and for immunogenicity and immune responsiveness. Results: Primary and metastatic tumors develop after orthotopic injection of M3-9-M into immunocompetent C57BL/6 mice, which mirror human ERMS with regard to histology, gene expression, and metastatic behavior. Whole cell vaccination using irradiated M3-9-M cells or M3-9-M-pulsed dendritic cells (DC)-induced tumor-specific T-cell responses that prevent tumor growth following low-dose tumor injection, and slow tumor growth following higher doses. Administration of anti-CD25 moAbs to deplete CD4 +CD25 +FOXP3 + regulatory T cells prior to tumor vaccination enhanced the potency of the ERMS tumor vaccine. Adoptive immunotherapy with M3-9-M primed T cells plus DC-based vaccination resulted in complete eradication of day 10 M3-9-M derived tumors. Conclusions: M3-9-M derived murine ERMS is immunogenic and immunoresponsive; regulatory T cells contribute to immune evasion by murine rhabdomyosarcoma. Adoptive immunotherapy with DC vaccination can eradicate low tumor burdens. Future work will seek to identify the tumor-associated antigens that mediate protective and therapeutic immunity in this model.

KW - Adoptive immunotherapy

KW - Embryonal rhabdomyosarcoma

KW - Immunotherapy

KW - Regulatory T cells

KW - Rhabdomyosarcoma

KW - Tumor antigen

KW - Tumor vaccine

UR - http://www.scopus.com/inward/record.url?scp=80052686056&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052686056&partnerID=8YFLogxK

U2 - 10.1002/pbc.23048

DO - 10.1002/pbc.23048

M3 - Article

C2 - 21462302

AN - SCOPUS:80052686056

VL - 57

SP - 921

EP - 929

JO - Pediatric Blood and Cancer

JF - Pediatric Blood and Cancer

SN - 1545-5009

IS - 6

ER -