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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

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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.

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Acknowledgments

These studies were funded in part by R01 CA 092344 (L.G.L.), R01 CA 140412 (L.G.L), 5P39 CA 022453 from National Cancer Institute, Translational Grants #6066-06 and #6092-09 from the Leukemia and Lymphoma Society (L.G.L), Susan G. Komen Foundation Translational Grant #BCTR0707125 (L.G.L), and Michigan Cell Therapy Center for Excellence Grant from the State of Michigan #1819, and startup funds from the Barbara Ann Karmanos Cancer Institute.

Conflict of interest

L.G.L. hold founder’s shares of Transtarget, Inc. The other authors have no financial conflict of interest.

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Authors and Affiliations

  1. Department of Oncology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, 723 Hudson Webber Cancer Research Center, 4100 John R, Detroit, MI, 48201, USA

    Archana Thakur, Dana Schalk, Zaid Al-Khadimi & Lawrence G. Lum

  2. Department of Oncology, Wayne State University and Karmanos Cancer Institute, Detroit, MI, 48201, USA

    Archana Thakur, Dana Schalk, Zaid Al-Khadimi & Lawrence G. Lum

  3. Department of Pathology, Wayne State University and Karmanos Cancer Institute, Detroit, MI, 48201, USA

    Sanila H. Sarkar & Fazlul H. Sarkar

  4. Department of Immunology and Microbiology, Wayne State University and Karmanos Cancer Institute, Detroit, MI, 48201, USA

    Lawrence G. Lum

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  1. Archana Thakur
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  2. Dana Schalk
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Correspondence to Archana Thakur.

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Thakur, A., Schalk, D., Sarkar, S.H. et al. 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. Cancer Immunol Immunother 61, 497–509 (2012). https://doi.org/10.1007/s00262-011-1116-1

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