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Lung cancer patients’ CD4+ T cells are activated in vitro by MHC II cell-based vaccines despite the presence of myeloid-derived suppressor cells

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Abstract

Background

Advanced non-small cell lung cancer (NSCLC) remains an incurable disease. Immunotherapies that activate patients’ T cells against resident tumor cells are being developed; however, these approaches may not be effective in NSCLC patients due to tumor-induced immune suppression. A major cause of immune suppression is myeloid-derived suppressor cells (MDSC). Because of the strategic role of CD4+ T lymphocytes in the activation of cytotoxic CD8+ T cells and immune memory, we are developing cell-based vaccines that activate tumor-specific CD4+ T cells in the presence of MDSC. The vaccines are NSCLC cell lines transfected with costimulatory (CD80) plus major histocompatibility complex class II (MHC II) genes that are syngeneic to the recipient. The absence of invariant chain promotes the presentation of endogenously synthesized tumor antigens, and the activation of MHC II-restricted, tumor-antigen-specific CD4+ T cells.

Methods

Potential vaccine efficacy was tested in vitro by priming and boosting peripheral blood mononuclear cells from ten NSCLC patients who had varying levels of MDSC. CD4+ T cell activation was quantified by measuring Type 1 and Type 2 cytokine release.

Results

The vaccines activated CD4+ T cells from all ten patients, despite the presence of CD33+CD11b+ MDSC. Activated CD4+ T cells were specific for NSCLC and did not cross-react with tumor cells derived from non-lung tissue or normal lung fibroblasts.

Conclusions

The NSCLC vaccines activate tumor-specific CD4+ T cells in the presence of potent immune suppression, and may be useful for the treatment of patients with NSCLC.

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Abbreviations

Ii:

Invariant chain

MDSC:

Myeloid-derived suppressor cells

NSCLC:

Non-small cell lung cancer

XRT:

Radiotherapy

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Acknowledgments

We thank Ms. Virginia Clements for her excellent technical assistance, Dr. Dean Mann for providing the PBMC, Dr. Pratima Sinha for her critique of the manuscript, and Ms. Chere Petty for help with the microscopy.

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Correspondence to Suzanne Ostrand-Rosenberg.

Additional information

Grant support: NIH R01 CA115880, R01 CA84232, Susan G. Komen Breast Cancer Foundation for the Cure BCTR0503885 (S. Ostrand-Rosenberg); NIH R01EY016486 (B. Ksander); Fight for Sight, Inc. post doctoral fellowship, Dutch foundations: Rotterdamse Vereniging Blindenbelangen, Stichting Blindenhulp, Stichting Blinden-Penning, Stichting Dondersfonds, Stichting Nelly Reef Fund, Gratama Stichting, Stichting Admiraal van Kinsbergen Fonds, and Foundation ‘De Drie Lichten.’ (J. Bosch); DOD Breast Cancer Program pre-doctoral fellowship DAMD17-03-0337 (J. Thompson).

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Srivastava, M.K., Bosch, J.J., Thompson, J.A. et al. Lung cancer patients’ CD4+ T cells are activated in vitro by MHC II cell-based vaccines despite the presence of myeloid-derived suppressor cells. Cancer Immunol Immunother 57, 1493–1504 (2008). https://doi.org/10.1007/s00262-008-0490-9

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