Mucin 1-specific immunotherapy in a mouse model of spontaneous breast cancer

Pinku Mukherjee, Cathy S. Madsen, Amelia R. Ginardi, Teresa L. Tinder, Fred Jacobs, Joanne Parker, Babita Agrawal, B. Michael Longenecker, Sandra J Gendler

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Human mucin 1 (MUC1) is an epithelial mucin glycoprotein that is over-expressed in 90% of all adenocarcinomas including breast, lung, pancreas, prostate, stomach, colon, and ovary. MUC1 is a target for immune intervention, because, in patients with solid adenocarcinomas, low-level cellular and humoral immune responses to MUC1 have been observed, which are not sufficiently strong to eradicate the growing tumor. The hypothesis for this study is that enhancing MUC1-specific immunity will result in antitumor immunity. To test this, the authors have developed a clinically relevant breast cancer model that demonstrates peripheral and central tolerance to MUC1 and develops spontaneous tumors of the mammary gland. In these mice, the authors tested a vaccine formulation comprised of liposomal-MUC1 lipopeptide and human recombinant interleukin-2. Results indicate that when compared with untreated mice, immunized mice develop T cells that express intracellular IFN-γ, are reactive with MHC class I H-2Db/MUC1 tetramer, and are cytotoxic against MUC1-expressing tumor cells in vitro. The presence of MUC1-specific CTL did not translate into a clinical response as measured by time of tumor onset, tumor burden, and survival. The authors demonstrate that some of the immune-evasion mechanisms used by the tumor cells include downregulation of MHC-class I molecule, expression of TGF-β2, and decrease in IFN-γ -expressing effector T cells as tumors progress. Finally, utilizing an injectable breast cancer model, the authors show that targeting a single tumor antigen may not be an effective antitumor treatment, but that immunization with dendritic cells fed with whole tumor lysate is effective in breaking tolerance and protecting mice from subsequent tumor challenge. A physiologically relevant spontaneous breast cancer model has been developed to test improved immunotherapeutic approaches.

Original languageEnglish (US)
Pages (from-to)47-62
Number of pages16
JournalJournal of Immunotherapy
Volume26
Issue number1
DOIs
StatePublished - Jan 2003

Fingerprint

Mucin-1
Immunotherapy
Breast Neoplasms
Neoplasms
Immunity
Adenocarcinoma
Central Tolerance
Peripheral Tolerance
Lipopeptides
T-Lymphocytes
Immune Evasion
Neoplasm Antigens
Mucins
Human Mammary Glands
Humoral Immunity
Tumor Burden
Cellular Immunity
Dendritic Cells
Interleukin-2
Prostate

Keywords

  • Immune evasion mechanisms
  • MUC1-specific cytotoxic T lymphocytes
  • Spontaneous mouse models of cancer
  • Tolerance
  • Transgenic mice

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Immunology

Cite this

Mucin 1-specific immunotherapy in a mouse model of spontaneous breast cancer. / Mukherjee, Pinku; Madsen, Cathy S.; Ginardi, Amelia R.; Tinder, Teresa L.; Jacobs, Fred; Parker, Joanne; Agrawal, Babita; Longenecker, B. Michael; Gendler, Sandra J.

In: Journal of Immunotherapy, Vol. 26, No. 1, 01.2003, p. 47-62.

Research output: Contribution to journalArticle

Mukherjee, P, Madsen, CS, Ginardi, AR, Tinder, TL, Jacobs, F, Parker, J, Agrawal, B, Longenecker, BM & Gendler, SJ 2003, 'Mucin 1-specific immunotherapy in a mouse model of spontaneous breast cancer', Journal of Immunotherapy, vol. 26, no. 1, pp. 47-62. https://doi.org/10.1097/00002371-200301000-00006
Mukherjee P, Madsen CS, Ginardi AR, Tinder TL, Jacobs F, Parker J et al. Mucin 1-specific immunotherapy in a mouse model of spontaneous breast cancer. Journal of Immunotherapy. 2003 Jan;26(1):47-62. https://doi.org/10.1097/00002371-200301000-00006
Mukherjee, Pinku ; Madsen, Cathy S. ; Ginardi, Amelia R. ; Tinder, Teresa L. ; Jacobs, Fred ; Parker, Joanne ; Agrawal, Babita ; Longenecker, B. Michael ; Gendler, Sandra J. / Mucin 1-specific immunotherapy in a mouse model of spontaneous breast cancer. In: Journal of Immunotherapy. 2003 ; Vol. 26, No. 1. pp. 47-62.
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