Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1

Caroline Imbert,Céline Colacios,Stéphane Carpentier,Bruno Ségui,Marlène Marcellin,Anne Gonzalez De Peredo,Julia Gilhodes,Thomas Filleron,Sophie Tartare‐Deckert ,Odile Burlet‐Schiltz ,Florent Puisset,Florie Bertrand,Nicolas Meyer,E Martin ,Anne Montfort,Marine Fraisse,Nathalie Andrieu‐Abadie ,Thierry Levade,Pierre Brousset,Virginie Garcia,Philippe Rochaix,Laurence Lamant,Elie Marcheteau

doi:10.1038/s41467-019-14218-7

Abstract

Immune checkpoint inhibitors (ICIs) have dramatically modified the prognosis of several advanced cancers, however many patients still do not respond to treatment. Optimal results might be obtained by targeting cancer cell metabolism to modulate the immunosuppressive tumor microenvironment. Here, we identify sphingosine kinase-1 (SK1) as a key regulator of anti-tumor immunity. Increased expression of SK1 in tumor cells is significantly associated with shorter survival in metastatic melanoma patients treated with anti-PD-1. Targeting SK1 markedly enhances the responses to ICI in murine models of melanoma, breast and colon cancer. Mechanistically, SK1 silencing decreases the expression of various immunosuppressive factors in the tumor microenvironment to limit regulatory T cell (Treg) infiltration. Accordingly, a SK1-dependent immunosuppressive signature is also observed in human melanoma biopsies. Altogether, this study identifies SK1 as a checkpoint lipid kinase that could be targeted to enhance immunotherapy.

Highlights

Immune checkpoint inhibitors (ICIs) have dramatically modified the prognosis of several advanced cancers, many patients still do not respond to treatment
Analysis of two different cohorts from the Oncomine database indicated that SPHK1 transcript levels were higher in human primary melanomas as compared to nevi (Fig. 1a, left panel); SPHK1 expression was further increased in metastatic melanomas (Fig. 1a, right panel), suggesting that SPHK1 expression might be associated with melanoma progression
In order to evaluate whether SPHK1 expression was related to the therapeutic outcome in advanced melanoma patients receiving anti-PD-1 therapy (Table 1), we analyzed SPHK1 messenger RNA expression in tumor biopsies by in situ hybridization using the RNAscope technology

Summary

Introduction

Immune checkpoint inhibitors (ICIs) have dramatically modified the prognosis of several advanced cancers, many patients still do not respond to treatment. Increased expression of SK1 in tumor cells is significantly associated with shorter survival in metastatic melanoma patients treated with anti-PD-1. The recent success of immunotherapy in melanoma relates to the use of monoclonal antibodies directed against the immune checkpoints such as programmed cell death protein-1 (anti-PD-1; pembrolizumab, nivolumab) and cytotoxic T-lymphocyte-associated protein-4 (anti-CTLA-4; ipilimumab). These immune checkpoint inhibitors (ICI) have demonstrated significant clinical efficacy in metastatic melanoma by reversing effector T-cell dysfunction and exhaustion, thereby enhancing their anti-tumoral properties[1]. We observe that high expression of SK1 in tumor cells is associated with shorter survival in melanoma patients treated with anti-PD-1. That combining ICI and SK1 antagonism may represent the basis for innovative anti-melanoma therapies

Methods

Results

Conclusion