Adoptive transfer of HER2/neu-specific T cells expanded with alternating gamma chain cytokines mediate tumor regression when combined with the depletion of myeloid-derived suppressor cells

  • Johanna K. Morales
  • Maciej Kmieciak
  • Laura Graham
  • Marta Feldmesser
  • Harry D. Bear
  • Masoud H. Manjili
Original Article

Abstract

Adoptive immunotherapy (AIT) using ex vivo-expanded HER-2/neu-specific T cells has shown initial promising results against disseminated tumor cells in the bone marrow. However, it has failed to promote objective responses against primary tumors. We report for the first time that alternating gamma chain cytokines (IL-2, IL-7 and IL-15) ex vivo can expand the neu-specific lymphocytes that can kill breast tumors in vitro. However, the anti-tumor efficacy of these neu-specific T cells was compromised by the increased levels of myeloid-derived suppressor cells (MDSC) during the premalignant stage in FVBN202 transgenic mouse model of breast carcinoma. Combination of AIT with the depletion of MDSC, in vivo, resulted in the regression of neu positive primary tumors. Importantly, neu-specific antibody responses were restored only when AIT was combined with the depletion of MDSC. In vitro studies determined that MDSC caused inhibition of T cell proliferation in a contact-dependent manner. Together, these results suggest that combination of AIT with depletion or inhibition of MDSC could lead to the regression of mammary tumors.

Keywords

Adoptive immunotherapy Breast cancer Myeloid-derived suppressor cells HER-2/neu Gamma chain cytokines 

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Johanna K. Morales
    • 1
  • Maciej Kmieciak
    • 1
  • Laura Graham
    • 2
  • Marta Feldmesser
    • 3
  • Harry D. Bear
    • 2
  • Masoud H. Manjili
    • 1
  1. 1.Department of Microbiology and Immunology, VCU School of MedicineMassey Cancer CenterRichmondUSA
  2. 2.Department of Surgery, VCU School of MedicineMassey Cancer CenterRichmondUSA
  3. 3.Department of MedicineAlbert Einstein College of MedicineBronxUSA

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