Survival of metastatic melanoma patients after dendritic cell vaccination correlates with expression of leukocyte phosphatidylethanolamine-binding protein 1/Raf kinase inhibitory protein

Sonja I Buschow,Gerold Schuler,Matteo Ramazzotti,I Jolanda M De Vries,Stanleyson V Hato,Nikolaus Romani,Jonathan M Austyn,Dilair Baban,Harm Westdorp,Jiannis Ragoussis,Georg Weinlich,Carl G Figdor,Duccio Cavalieri,Luca Beltrame,Irene Stefanini,Van Anh Nguyen,Eva Ellebæk ,Inge Reinieren-Beeren ,Lucie Heinzerling ,Inge Marie Svane ,Stefanie Groß ,Beatrice Schuler‐Thurner

doi:10.18632/oncotarget.18698

Abstract

Immunotherapy for metastatic melanoma offers great promise but, to date, only a subset of patients have responded. There is an urgent need to identify ways of allocating patients to the most beneficial therapy, to increase survival and decrease therapy-associated morbidity and costs. Blood-based biomarkers are of particular interest because of their straightforward implementation in routine clinical care. We sought to identify markers for dendritic cell (DC) vaccine-based immunotherapy against metastatic melanoma through gene expression analysis of peripheral blood mononuclear cells. A large-scale microarray analysis of 74 samples from two treatment centers, taken directly after the first round of DC vaccination, was performed. We found that phosphatidylethanolamine binding protein 1 (PEBP1)/Raf Kinase inhibitory protein (RKIP) expression can be used to identify a significant proportion of patients who performed poorly after DC vaccination. This result was validated by q-PCR analysis on blood samples from a second cohort of 95 patients treated with DC vaccination in four different centers. We conclude that low PEBP1 expression correlates with poor overall survival after DC vaccination. Intriguingly, this was only the case for expression of PEBP1 after, but not prior to, DC vaccination. Moreover, the change in PEBP1 expression upon vaccination correlated well with survival. Further analyses revealed that PEBP1 expression positively correlated with genes involved in T cell responses but inversely correlated with genes associated with myeloid cells and aberrant inflammation including STAT3, NOTCH1, and MAPK1. Concordantly, PEBP1 inversely correlated with the myeloid/lymphoid-ratio and was suppressed in patients suffering from chronic inflammatory disease.

Highlights

Metastatic melanoma is one of the most devastating types of cancers in terms of potential life-years lost and affects a growing number of patients each year [1, 2]
These therapies are based on: 1) antagonists of molecules that suppress pre-existing anti-tumor immune responses, so-called immune checkpoint inhibitors such as antiCTLA-4 and anti-PD-1/PD-L1 antibodies; 2) delivery of autologous ex vivo expanded tumor infiltrating lymphocytes to boost anti-tumor T cell response; 3) oncolytic viruses injected into metastases to lyse tumor cells and enhance immune responses; and 4) ex vivo or in vivo targeting of dendritic cell (DCs) to initiate and/or boost tumor antigen-specific immune responses
We here describe phosphatidylethanolamine binding protein 1 (PEBP1) as a novel gene whose low expression on blood leukocytes is associated with poor survival in metastatic melanoma patients receiving DC therapy

Summary

Introduction

Metastatic melanoma is one of the most devastating types of cancers in terms of potential life-years lost and affects a growing number of patients each year [1, 2]. There are different types of immunotherapy that may offer long-term benefit for melanoma patients These therapies are based on: 1) antagonists of molecules that suppress pre-existing anti-tumor immune responses, so-called immune checkpoint inhibitors such as antiCTLA-4 (ipilimumab) and anti-PD-1/PD-L1 antibodies (nivolumab/pembrolizumab/atezolizumab); 2) delivery of autologous ex vivo expanded tumor infiltrating lymphocytes to boost anti-tumor T cell response; 3) oncolytic viruses injected into metastases to lyse tumor cells and enhance immune responses; and 4) ex vivo or in vivo targeting of dendritic cell (DCs) to initiate and/or boost tumor antigen-specific immune responses (reviewed in [3, 4]). Mechanism of action-based markers, derived from our understanding of why specific treatments are beneficial or not in certain patient populations, have a high potential [7]

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Conclusion