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The absence of invariant chain in MHC II cancer vaccines enhances the activation of tumor-reactive type 1 CD4+ T lymphocytes

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Abstract

Activation of tumor-reactive T lymphocytes is a promising approach for the prevention and treatment of patients with metastatic cancers. Strategies that activate CD8+ T cells are particularly promising because of the cytotoxicity and specificity of CD8+ T cells for tumor cells. Optimal CD8+ T cell activity requires the co-activation of CD4+ T cells, which are critical for immune memory and protection against latent metastatic disease. Therefore, we are developing “MHC II” vaccines that activate tumor-reactive CD4+ T cells. MHC II vaccines are MHC class I+ tumor cells that are transduced with costimulatory molecules and MHC II alleles syngeneic to the prospective recipient. Because the vaccine cells do not express the MHC II-associated invariant chain (Ii), we hypothesized that they will present endogenously synthesized tumor peptides that are not presented by professional Ii+ antigen presenting cells (APC) and will therefore overcome tolerance to activate CD4+ T cells. We now report that MHC II vaccines prepared from human MCF10 mammary carcinoma cells are more efficient than Ii+ APC for priming and boosting Type 1 CD4+ T cells. MHC II vaccines consistently induce greater expansion of CD4+ T cells which secrete more IFNγ and they activate an overlapping, but distinct repertoire of CD4+ T cells as measured by T cell receptor Vβ usage, compared to Ii+ APC. Therefore, the absence of Ii facilitates a robust CD4+ T cell response that includes the presentation of peptides that are presented by traditional APC, as well as peptides that are uniquely presented by the Ii− vaccine cells.

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Acknowledgments

Grant Support: NIH R01CA84232 and R01CA115880 (SOR); NIH R01EY016486 (BRK). JAT is supported by DOD Breast Cancer Program pre-doctoral fellowship DAMD17-03-0337. JJB is partially supported by a Fight for Sight, Inc., post doctoral fellowship, and the following 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.’ We thank Dr. Dean Mann for providing the healthy donor PBMC.

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Authors and Affiliations

  1. Department of Biological Sciences, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD, 21250, USA

    James A. Thompson, Minu K. Srivastava, Jacobus J. Bosch, Virginia K. Clements & Suzanne Ostrand-Rosenberg

  2. The Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, MA, USA

    Bruce R. Ksander

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  1. James A. Thompson
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  2. Minu K. Srivastava
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  6. Suzanne Ostrand-Rosenberg
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Correspondence to Suzanne Ostrand-Rosenberg.

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Thompson, J.A., Srivastava, M.K., Bosch, J.J. et al. The absence of invariant chain in MHC II cancer vaccines enhances the activation of tumor-reactive type 1 CD4+ T lymphocytes. Cancer Immunol Immunother 57, 389–398 (2008). https://doi.org/10.1007/s00262-007-0381-5

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  • DOI: https://doi.org/10.1007/s00262-007-0381-5

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