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Intrinsically de-sialylated CD103+ CD8 T cells mediate beneficial anti-glioma immune responses

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Background

Cancer vaccines reproducibly cure laboratory animals and reveal encouraging trends in brain tumor (glioma) patients. Identifying parameters governing beneficial vaccine-induced responses may lead to the improvement of glioma immunotherapies. CD103+ CD8 T cells dominate post-vaccine responses in human glioma patients for unknown reasons, but may be related to recent thymic emigrant (RTE) status. Importantly, CD8 RTE metrics correlated with beneficial immune responses in vaccinated glioma patients.

Methods

We show by flow cytometry that murine and human CD103+ CD8 T cells respond better than their CD103− counterparts to tumor peptide-MHC I (pMHC I) stimulation in vitro and to tumor antigens on gliomas in vivo.

Results

Glioma responsive T cells from mice and humans both exhibited intrinsic de-sialylation-affecting CD8 beta. Modulation of CD8 T cell sialic acid with neuraminidase and ST3Gal-II revealed de-sialylation was necessary and sufficient for promiscuous binding to and stimulation by tumor pMHC I. Moreover, de-sialylated status was required for adoptive CD8 T cells and lymphocytes to decrease GL26 glioma invasiveness and increase host survival in vivo. Finally, increased tumor ST3Gal-II expression correlated with clinical vaccine failure in a meta-analysis of high-grade glioma patients.

Conclusions

Taken together, these findings suggest that de-sialylation of CD8 is required for hyper-responsiveness and beneficial anti-glioma activity by CD8 T cells. Because CD8 de-sialylation can be induced with exogenous enzymes (and appears particularly scarce on human T cells), it represents a promising target for clinical glioma vaccine improvement.

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Abbreviations

CNS:

Central nervous system

DC:

Dendritic cell

GBM:

Glioblastoma multiforme

IFN-γ:

Interferon-gamma

IL-12:

Interleukin-12

MHC I:

Major histocompatibility complex class I

PNA:

Peanut agglutinin

RTE:

Recent thymic emigrant

TCR:

T cell receptor

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Acknowledgments

The authors are grateful to all the patients and their families who contributed tumor tissue and/or participated in clinical trials included in this study. This work was supported by the Maxine Dunitz Neurosurgical Institute and in part by Grants from the Joseph Drown Foundation and National Institutes of Health [NS054162-01] to Christopher J. Wheeler.

Conflict of interest

Keith L. Black has ownership and stock interests in ImmunoCellular Therapeutics, Inc. Christopher J. Wheeler and Keith L. Black are holders of the following relevant patents: US patent 7,705,010B2, “Use of Minoxidil Sulfate as an Anti-Cancer Drug,” which describes combining DC vaccination with minoxidil sulfate to treat high-grade gliomas. Patent WO/2005/043155, “System and method for the treatment of cancer, including cancers of the central nervous system,” which describes combining DC vaccination with chemotherapy to treat high-grade gliomas. No other authors have conflicts or potential conflicts to declare.

Author information

Author notes

  1. Emmanuel Jouanneau

    Present address: Department of Neurosurgery, Neurological Hospital and INSERM 842 Research Unit, Claude Bernard University, Lyon, France

  2. Armen Mardiros

    Present address: Department of Cancer Immunotherapeutics and Tumor Immunology, City of Hope National Medical Center, Duarte, CA, 91010, USA

Authors and Affiliations

  1. Department of Neurosurgery, Cedars Sinai Medical Center, Advanced Health Sciences Pavilion, Maxine Dunitz Neurosurgical Institute, 127 S. San Vicente Blvd, Suite A8113, Los Angeles, CA, 90048, USA

    Emmanuel Jouanneau, Keith L. Black, Lucia Veiga, Ryan Cordner, Shyam Goverdhana, Yuying Zhai, Xiao-xue Zhang, Akanksha Panwar, Armen Mardiros, HongQiang Wang, Ashley Gragg, Mandana Zandian, Dwain K. Irvin & Christopher J. Wheeler

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Correspondence to Christopher J. Wheeler.

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Jouanneau, E., Black, K.L., Veiga, L. et al. Intrinsically de-sialylated CD103+ CD8 T cells mediate beneficial anti-glioma immune responses. Cancer Immunol Immunother 63, 911–924 (2014). https://doi.org/10.1007/s00262-014-1559-2

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