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

  • Archana Thakur
  • Dana Schalk
  • Sanila H. Sarkar
  • Zaid Al-Khadimi
  • Fazlul H. Sarkar
  • Lawrence G. Lum
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

Authors and Affiliations

  • Archana Thakur
    • 1
    • 2
  • Dana Schalk
    • 1
    • 2
  • Sanila H. Sarkar
    • 3
  • Zaid Al-Khadimi
    • 1
    • 2
  • Fazlul H. Sarkar
    • 3
  • Lawrence G. Lum
    • 1
    • 2
    • 4
  1. 1.Department of OncologyWayne State University School of Medicine and Barbara Ann Karmanos Cancer InstituteDetroitUSA
  2. 2.Department of OncologyWayne State University and Karmanos Cancer InstituteDetroitUSA
  3. 3.Department of PathologyWayne State University and Karmanos Cancer InstituteDetroitUSA
  4. 4.Department of Immunology and MicrobiologyWayne State University and Karmanos Cancer InstituteDetroitUSA