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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

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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.

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Acknowledgments

This work was supported by NIH R01 CA104757 grant (M. H. Manjili) and flow cytometry shared resources facility supported in part by the NIH grant P30CA16059. We thank Daniel Conrad and Jamie Sturgill for their assistance with purification of the anti-Gr1 antibody. We gratefully acknowledge the support of VCU Massey Cancer Centre and the Commonwealth Foundation for Cancer Research, Department of Defense Grant BC083048.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, VCU School of Medicine, Massey Cancer Center, Box 980035, 401 College Street, Richmond, VA, 23298, USA

    Johanna K. Morales, Maciej Kmieciak & Masoud H. Manjili

  2. Department of Surgery, VCU School of Medicine, Massey Cancer Center, Richmond, VA, 23298, USA

    Laura Graham & Harry D. Bear

  3. Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, 10461, USA

    Marta Feldmesser

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  1. Johanna K. Morales
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  2. Maciej Kmieciak
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  6. Masoud H. Manjili
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Correspondence to Masoud H. Manjili.

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J. K. Morales and M. Kmieciak have equally contributed to this work.

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Morales, J.K., Kmieciak, M., Graham, L. et al. 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. Cancer Immunol Immunother 58, 941–953 (2009). https://doi.org/10.1007/s00262-008-0609-z

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