Cytokine responsiveness of CD8(+) T cells is a reproducible biomarker for the clinical efficacy of dendritic cell vaccination in glioblastoma patients

Richard G Everson; Richard M Jin; Xiaoyan Wang; Michael Safaee; Rudi Scharnweber; Dominique N Lisiero; Horacio Soto; Linda M Liau; Robert M Prins

doi:10.1186/2051-1426-2-10

Cytokine responsiveness of CD8(+) T cells is a reproducible biomarker for the clinical efficacy of dendritic cell vaccination in glioblastoma patients

J Immunother Cancer. 2014 May 13:2:10. doi: 10.1186/2051-1426-2-10. eCollection 2014.

Authors

Richard G Everson^#¹, Richard M Jin^#¹, Xiaoyan Wang², Michael Safaee¹, Rudi Scharnweber¹, Dominique N Lisiero^{1

3}, Horacio Soto¹, Linda M Liau^{1

4

5}, Robert M Prins^{1

4

5

3}

Affiliations

¹ Departments of Neurosurgery, University of California Los Angeles, Los Angeles, CA 90095, USA.
² Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
³ Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁴ Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁵ Brain Research Institute, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA 90095, USA.

^# Contributed equally.

Abstract

Background: Immunotherapeutic approaches, such as dendritic cell (DC) vaccination, have emerged as promising strategies in the treatment of glioblastoma. Despite their promise, however, the absence of objective biomarkers and/or immunological monitoring techniques to assess the clinical efficacy of immunotherapy still remains a primary limitation. To address this, we sought to identify a functional biomarker for anti-tumor immune responsiveness associated with extended survival in glioblastoma patients undergoing DC vaccination.

Methods: 28 patients were enrolled and treated in two different Phase 1 DC vaccination clinical trials at UCLA. To assess the anti-tumor immune response elicited by therapy, we studied the functional responsiveness of pre- and post-vaccination peripheral blood lymphocytes (PBLs) to the immunostimulatory cytokines interferon-gamma (IFN-γ) and interleukin-2 (IL-2) in 21 of these patients for whom we had adequate material. Immune responsiveness was quantified by measuring downstream phosphorylation events of the transcription factors, STAT-1 and STAT-5, via phospho-specific flow cytometry.

Results: DC vaccination induced a significant decrease in the half-maximal concentration (EC-50) of IL-2 required to upregulate pSTAT-5 specifically in CD3(+)CD8(+) T lymphocytes (p < 0.045). Extended survival was also associated with an increased per cell phosphorylation of STAT-5 in cytotoxic T-cells following IL-2 stimulation when the median post/pre pSTAT-5 ratio was used to dichotomize the patients (p = 0.0015, log-rank survival; hazard ratio = 0.1834, p = 0.018). Patients whose survival was longer than two years had a significantly greater pSTAT-5 ratio (p = 0.015), but, contrary to our expectations, a significantly lower pSTAT-1 ratio (p = 0.038).

Conclusions: Our results suggest that monitoring the pSTAT signaling changes in PBL may provide a functional immune monitoring measure predictive of clinical efficacy in DC-vaccinated patients.

Keywords: Dendritic cells; Glioblastoma; Phospho-flow cytometry; T cells; Tumor immunity; pSTAT-5.

Abstract

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