Oncotarget

Research Papers:

Characterization of CD4+ T cells primed and boosted by MHCII primary uveal melanoma cell-based vaccines

Julia M. Kittler, Jonas Sommer, Anika Fischer, Sabine Britting, Margarete M. Karg, Barbara Bock, Imke Atreya, Ludwig M. Heindl, Andreas Mackensen and Jacobus J. Bosch _

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Oncotarget. 2019; 10:1812-1828. https://doi.org/10.18632/oncotarget.26737

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Abstract

Julia M. Kittler1, Jonas Sommer1, Anika Fischer2, Sabine Britting1, Margarete M. Karg1, Barbara Bock1, Imke Atreya2, Ludwig M. Heindl3, Andreas Mackensen1 and Jacobus J. Bosch1

1Department of Internal Medicine 5 – Hematology and Oncology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Erlangen, Germany

2Department of Internal Medicine 1 – Gastroenterology, Pneumology and Endocrinology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Erlangen, Germany

3Department of Ophthalmology and Center for Integrated Oncology (CIO) Cologne-Bonn, University of Cologne, Cologne, Germany

Correspondence to:

Jacobus J. Bosch, email: jacobus.bosch@uk-erlangen.de

Keywords: uveal melanoma; tumor immunity; T cell activation; CD4+ T cells; ICAM-1

Received: December 15, 2018     Accepted: February 09, 2019     Published: March 05, 2019

ABSTRACT

Uveal melanoma is the most common primary malignancy of the eye in adults. Despite significant improvements in treatment of the primary tumor, to date none of these therapies prevent metastatic disease or improve overall survival. We are exploring immunotherapeutic options for metastatic uveal melanoma using MHC II uveal melanoma cell-based vaccines that target the activation of tumor-reactive CD4+ T cells. Previously, we showed that these uveal melanoma cell-based vaccines activate CD4+ T cells within total peripheral blood lymphocytes (PBMC). Since PBMC include professional antigen presenting cells, we now demonstrate that Mel202/DR1/CD80 vaccine cells directly activate a diverse repertoire of purified, naïve CD4+ T cells. The activated CD4+ T cells proliferated, secreted high amounts of interferon gamma (IFNγ) and produced a heterogeneous profile of Th1, Th2 and Th17 cytokines. Analysis of the TCR-Vβ-repertoire showed that a polyclonal T cell response was induced, suggesting the capacity of vaccine-activated CD4+ T cells to target multiple tumor (neo)antigens. In addition, a subset of the responding CD4+ T cells expressed forkhead box protein P3 (FoxP3), indicating that although a regulatory component of the vaccine-activated CD4+ T cell response was induced, the anti-tumor vaccine response was not limited by these regulatory CD4+ T cells. Finally, Mel202/DR1/CD80 uveal melanoma vaccine cells expressed the intercellular adhesion molecule 1 (ICAM-1) that was pivotal for CD4+ T cell activation via lymphocyte function-associated antigen 1(LFA-1). In conclusion, MHC II uveal melanoma vaccines activate purified CD4+ T cells and may serve as a novel immunotherapy for uveal melanoma patients.


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