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

Abstract

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1140-9) contains supplementary material, which is available to authorized users.

Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients

“…Although different vaccination trials have reported a lack of a real advantage in the anti-tumor efficacy, 29 , 30 also in combination with the CTLA-4 blockade, 31 the gp100 209-217 (210M)-based vaccination, in combination with IL-2, showed clinical benefits in metastatic melanoma patients. 32 , 33 At TCR level, Schrama et al found the expansion of an oligoclonal gp100 210M-specific TCR repertoire from two patients receiving DTIC alone or in combination with low doses of IFN-α.…”

Advances in Proteomic Techniques for Cytokine Analysis: Focus on Melanoma Research

“…Bead-based arrays find broad applications in cancer research, including melanoma research. Immunotherapeutic predictive or prognostic values of serum cytokines were tested in melanoma patients treated by adjuvant interferon [ 128 ] and ipilimumab [ 69 ]. Blood plasma cytokines have been analysed in patients with unresectable in-transit extremity melanoma, treated by isolated limb infusion with melphalan [ 129 ].…”

“…In a study of therapeutic effects of ipilimumab (monoclonal antibody targeting CTLA-4), an increased secretion of IL-1β, IL-2, IL-4, IL-5, IL-7, IL-8, IL-10, IL-13, IL-17, Granulocyte-colony stimulating factor (G-CSF), Granulocyte-macrophage colony-stimulating factor (GM-CSF), HGF, IFNγ, Monocyte chemoattractant protein 1 (MCP-1, CCL2) and VEGF from peripheral blood mononuclear cells (PBMCs) showed a trend towards better recurrence free survival in melanoma [ 69 ]. Interestingly, these cytokines belong to various functional groups with pro-inflammatory and anti-inflammatory effects [ 69 ]. Possibilities of therapeutic administration of cytokines to induce anti-tumour responses in melanoma have been reviewed by Xu et al [ 70 ].…”

Frontiers in pigment cell and melanoma research

“…In addition, the combination of ipilimumab and nivolumab has been approved in patients without B-Raf proto-oncogene, serine/threonine kinase (BRAF) activating mutations and metastatic or unresectable melanoma. Checkpoint regulators on T cells play vital roles in limiting adaptive immune responses and preventing autoimmune and auto-inflammatory reactivity in the normal host (Najjar et al, 2017). In cancer patients, PD-1 expression can be very high on T cells in the tumor microenvironment, and PD-L1, its primary ligand, is variably expressed on tumor cells and antigen-presenting cells within tumors, providing a potent inhibitory influence within the tumor microenvironment.…”