Melanoma antigen-specific effector T cell cytokine secretion patterns in patients treated with ipilimumab

Journal of Translational Medicine

Research

Fei Ding¹  Yan Lin¹  Ahmad A. Tarhini²  Yana G. Najjar³  Robert VanderWeele³  Lisa H. Butterfield⁴ 

[1] Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA;Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh, University of Pittsburgh Cancer Institute, 5150 Centre Avenue (555), 15232, Pittsburgh, PA, USA;University of Pittsburgh Medical Center, Pittsburgh, PA, USA;University of Pittsburgh, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA;

关键词: Neoadjuvant;    Melanoma;    Ipilimumab;    Cytokines;   

DOI  :  10.1186/s12967-017-1140-9

 received in 2016-11-23, accepted in 2017-02-04,  发布年份 2017

来源: Springer

【 摘 要 】

Background In a previously reported study, patients with regionally advanced melanoma were treated with neoadjuvant ipilimumab (ipi) (Tarhini in PLoS ONE 9(2): e87705, 3). Significant changes in circulating myeloid derived suppressor cells (MDSC), regulatory T cells (Treg) and peptide specific type I CD4+ and CD8+ T cells were noted at week 6 that correlated with clinical outcome. Characterization of antigen-specific effector T cell secreted cytokines may shed insights into ipi associated T cell activation and function.MethodsPatients were treated with neoadjuvant ipi (10 mg/kg every 3 weeks ×2) administered intravenously before and after surgery. Peripheral blood mononuclear cells (PBMC) that were collected at baseline and week 6 (after ipi) were tested here. Each sample was divided into 5 groups and stimulated with controls or shared melanoma antigen overlapping peptide pools (NY-ESO 1, gp-100, MART-1). Secreted cytokines, chemokines and growth factors were assessed using Luminex. Cytokine expression levels between the 3 antigen groups were compared using the Wilcox rank-sum test.ResultsSeventeen cytokines were differentially expressed with stimulation by each antigen at baseline (p value <0.05): IL1β, MIP1β, IL1RA, VEGF, IL13, IL17, MIP1α, GM-CSF, MCP1, IL5, IL2R, IL4, IL10, IFNγ, TNFα, IL8 and IL2. At week 6, 15 cytokines were differentially expressed (p < 0.05): IL1β, VEGF, G-CSF, HGF, IL13, IL17, GM-CSF, MCP1, IL5, IL7, IL4, IL10, IFNγ, IL8 and IL2. Patients were later clustered based on cytokine expression levels at baseline and at week 6, and recurrence free survival (RFS) was compared. Clear differences in RFS were noted based on cytokine level clustering both at baseline and at week 6: Patients whose PBMCs secreted more cytokines in response to NY-ESO-1 showed a trend towards better RFS.ConclusionsPBMCs of patients treated with ipi secreted significantly more cytokines, chemokines and growth factors in response to NY-ESO-1 than to gp-100 or MART-1. These cytokines belonged to different functional groups, including inflammatory, type 1, type 2 and regulatory, that warrant further study. Patients whose PBMCs secreted more cytokines (particularly in response to NY-ESO-1) tended to have better RFS, supporting further exploration in terms of therapeutic predictive value.

【 授权许可】

CC BY   
© The Author(s) 2017