Immunological monitoring for prediction of clinical response to antitumor vaccine therapy.

Irina N Mikhaylova,Mikhail V Kiselevsky,Evgeny A Cheremushkin,Valeria V Nazarova,George Z Chkadua,Kermen A Parsunkova,Alvina A Molodyk,Robert Sh Beabelashvili,Natalia V Balatskaya,Olga S Burova,Lidia F Morozova,Irina Zh Shubina,Vadim I Pospelov,Lev V Demidov,Natalia N Petenko,Anastasia S Vihrova,Dmitrii K Chebanov

doi:10.18632/oncotarget.25274

Abstract

Immunotherapy has shown promising results in a variety of cancers, including melanoma. However, the responses to therapy are usually heterogeneous, and understanding the factors affecting clinical outcome is still not achieved. Here, we show that immunological monitoring of the vaccine therapy for melanoma patients may help to predict the clinical course of the disease.We studied cytokine profile of cellular Th1 (IL-2, IL-12, IFN-γ) and humoral Th2 (IL-4, IL-10) immune response, vascular endothelial growth factor (VEGFA), transforming growth factor-β 2 (TGF-β 2), S100 protein (S100A1B and S100BB), adhesion molecule CD44 and serum cytokines β2-microglobulin to analyze different peripheral blood mononuclear cell subpopuations of patients treated with dendritic vaccines and/or cyclophosphamide in melanoma patients in the course of adjuvant treatment.The obtained data indicate predominance of cellular immunity in the first adjuvant group of patients with durable time to progression and shift to humoral with low cellular immunity in patients with short-term period to progression (increased levels of IL-4 and IL- 10). Beta-2 microglobulin was differentially expressed in adjuvant subgroups: its higher levels correlated with shorter progression-free survival and the total follow-up time. Immunoregulatory index was overall higher in patients with disease progression compared to the group of patients with no signs of disease progression.

Highlights

Immunotherapeutic approaches are at the forefront of cancer treatment, and it has been accepted that patient’s own immune system often provides the best weapon to inactivate malignant cancer cells in the body
We studied cytokine profile of cellular Th1 (IL-2, IL-12, IFN-γ) and humoral Th2 (IL-4, IL-10) immune response, vascular endothelial growth factor (VEGFA), transforming growth factor-β 2 (TGF-β 2), S100 protein (S100A1B and S100BB), adhesion molecule CD44 and serum cytokines β2-microglobulin to analyze different peripheral blood mononuclear cell subpopuations of patients treated with dendritic vaccines and/or cyclophosphamide in melanoma patients in the course of adjuvant treatment
The T-cell effector immune response is realized via polarization of Th1 cells and secretion of IFN-γ, IL-2 and IL-12 cytokines, while the humoral immune response is characterized with the predominance of Th2 cells and cytokines like IL-4 and IL-10

Summary

Introduction

Immunotherapeutic approaches are at the forefront of cancer treatment, and it has been accepted that patient’s own immune system often provides the best weapon to inactivate malignant cancer cells in the body. The responses to such therapy (which includes dendritic cell vaccine, PD-1 inhibitory therapy and others aimed at restoring anti-cancer immune function) are very heterogeneous, and ability to monitor and have prognostic markers for such treatments is necessary. Inhibition of IL-2 causes the accumulation of immunosuppressive substances like gangliosides, which are produced by melanoma cells and inhibit the production of IL-2 by directly damaging the molecules [3, 4]. IL-12 induces Th0-Th1 polarization and Th1-cells secrete IFN-γ. Dendritic cells (DC) and macrophages are the major producers of IL-12. There are both positive and negative dynamics of IL-12 during immunotherapy in melanoma patients described earlier [5]. The key role of IL-6 as a negative prognosis factor of overall survival was repeatedly reported [6]

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