Cancer Immunology, Immunotherapy

, Volume 61, Issue 4, pp 497–509

A Th1 cytokine–enriched microenvironment enhances tumor killing by activated T cells armed with bispecific antibodies and inhibits the development of myeloid-derived suppressor cells

Authors

    • Department of OncologyWayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute
    • Department of OncologyWayne State University and Karmanos Cancer Institute
  • Dana Schalk
    • Department of OncologyWayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute
    • Department of OncologyWayne State University and Karmanos Cancer Institute
  • Sanila H. Sarkar
    • Department of PathologyWayne State University and Karmanos Cancer Institute
  • Zaid Al-Khadimi
    • Department of OncologyWayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute
    • Department of OncologyWayne State University and Karmanos Cancer Institute
  • Fazlul H. Sarkar
    • Department of PathologyWayne State University and Karmanos Cancer Institute
  • Lawrence G. Lum
    • Department of OncologyWayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute
    • Department of OncologyWayne State University and Karmanos Cancer Institute
    • Department of Immunology and MicrobiologyWayne State University and Karmanos Cancer Institute
Original article

DOI: 10.1007/s00262-011-1116-1

Cite this article as:
Thakur, A., Schalk, D., Sarkar, S.H. et al. Cancer Immunol Immunother (2012) 61: 497. doi:10.1007/s00262-011-1116-1

Abstract

In this study, we investigated whether activated T cells (ATC) armed with bispecific antibodies (aATC) can inhibits tumor growth and MDSC development in a Th1 cytokine–enriched (IL-2 and IFN-γ) microenvironment. Cytotoxicity mediated by aATC was significantly higher (P < 0.001) against breast cancer cell lines in the presence of Th1 cytokines as compared with control co-cultures. In the presence of aATC, CD33+/CD11b+/CD14/HLA-DR MDSC population was reduced significantly under both control (P < 0.03) and Th1-enriched (P < 0.036) culture conditions. Cytokine analysis in the culture supernatants showed high levels of MDSC suppressive chemokines CXCL9 and CXCL10 in Th1-enriched culture supernatants with highly significant increase (P < 0.001) in the presence of aATC. Interestingly, MDSC recovered from co-cultures without aATC showed potent ability to suppress activated T-cell-mediated cytotoxicity (P < 0.001), IFN-γ production (P < 0.01) and T-cell proliferation (P < 0.05) compared to those recovered from aATC-containing co-cultures. These data suggest that aATC can mediate enhanced killing of tumor cells and may suppress MDSC and Treg differentiation, and presence of Th1 cytokines potentiates aATC-induced suppression of MDSC, suggesting that Th1-enriching immunotherapy may be beneficial in cancer treatment.

Keywords

3D culture modelBreast cancerActivated T cellsBispecific antibodyPeripheral blood mononuclear cellsMyeloid-derived suppressor cells

Copyright information

© Springer-Verlag 2011