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

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

doi:10.1038/s41467-019-14218-7

Cited by 95 publications

(101 citation statements)

References 54 publications

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“…There are many examples of SK1 upregulation at the mRNA and protein level, which is often associated with poor prognosis including reduced survival and earlier disease recurrence in cancer patients [2]. Recent examples include melanoma [62], papillary thyroid carcinoma [84], non-small cell lung cancer [85], triple-negative breast cancer [86] and colorectal cancer [87]. This is consistent with the ability of SK1 to promote cell survival, proliferation and neoplastic transformation and supports the therapeutic potential of SK1 inhibitors.…”

Section: Sk1/sk2 and Cancermentioning

confidence: 58%

“…Silencing SK1 decreased TGFβ, IL10, CCL17 and CCL22 levels in the tumour microenvironment to limit Treg infiltration, accompanied by downregulation of prostaglandin E synthase and PGE2 formation. Furthermore, SK1 silencing markedly enhances responses to anti‐PD‐1 and to other immune checkpoint inhibitors (ICIs) in murine models of melanoma, breast and colon cancer, thereby reducing tumour growth [62]. The activation of natural killer T (NKT) cells (by glycolipid antigens on CD1d) is also increased by knockdown of SK1 or antagonism of S1P 1 in mantle cell lymphoma, an aggressive subtype of non‐Hodgkin's lymphoma that is associated with increased S1P levels.…”

Section: Role Of S1p In Protumorigenic Inflammation and Immune Signalmentioning

confidence: 99%

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Recent advances in the role of sphingosine 1‐phosphate in cancer

Pyne

2020

FEBS Letters

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Sphingosine 1-phosphate (S1P) is a bioactive lipid that binds to a family of G protein-coupled receptors (S1P 1-5) and intracellular targets, such as HDAC1/ 2, that are functional in normal and pathophysiologic cell biology. There is a significant role for sphingosine 1-phosphate in cancer underpinning the socalled hallmarks, such as transformation and replicative immortality. In this review, we survey the most recent developments concerning the role of sphingosine 1-phosphate receptors, sphingosine kinase and S1P lyase in cancer and the prognostic indications of these receptors and enzymes in terms of diseasespecific survival and recurrence. We also provide evidence for identification of new therapeutic approaches targeting sphingosine 1-phosphate to prevent neovascularisation, to revert aggressive and drug-resistant cancers to more amenable forms sensitive to chemotherapy, and to induce cytotoxicity in cancer cells. Finally, we briefly describe current advances in the development of isoform-specific inhibitors of sphingosine kinases for potential use in the treatment of various cancers, where these enzymes have a predominant role. This review will therefore highlight sphingosine 1-phosphate signalling as a promising translational target for precision medicine in stratified cancer patients.

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Section: Sk1/sk2 and Cancermentioning

confidence: 58%

Section: Role Of S1p In Protumorigenic Inflammation and Immune Signalmentioning

confidence: 99%

Recent advances in the role of sphingosine 1‐phosphate in cancer

Pyne

2020

FEBS Letters

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“…Another analysis showed that in melanoma tumors, SK1 knockdown significantly reduced the production of various immunosuppressive cytokines, such as TGF‐β, IL‐10, CCL17, and CCL22, which was consistent with the explanation of the significant decrease in tumor infiltration of Treg. When SK1 was silenced, PGEs was significantly reduced, leading to a significant reduction in the production of PGE2 (Prostaglandin E2 synthase), and enhancing the therapeutic response of melanoma to PD‐1/PD‐L1 monoclonal antibody 247 . The combination of ICB and SK1 antagonists may be an innovative anticancer therapy option.…”

Section: Pd‐1/pd‐l1 Resistance and Cell Metabolism And Metabolitesmentioning

confidence: 99%

Study and analysis of antitumor resistance mechanism of PD1/PD‐L1 immune checkpoint blocker

Wang

2020

Cancer Medicine

100

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Immunocheckpoint proteins of tumor infiltrating lymphocytes play an important role in tumor prognosis in the course of tumor clinicopathology. PD‐1 (Programmed cell death protein 1) is an important immunosuppressive molecule. By binding to PD‐L1 (programmed cell death‐ligand 1), it blocks TCR and its costimulus signal transduction, inhibits the activation and proliferation of T cells, depletes the function of effector T cells, and enables tumor cells to achieve immune escape. In recent years, immunocheckpoint blocking therapy targeting the PD‐1/PD‐L1 axis has achieved good results in a variety of malignant tumors, pushing tumor immunotherapy to a new milestone, such as anti‐PD‐1 monoclonal antibody Nivolumab, Pembrolizumab, and anti‐PD‐L1 monoclonal antibody Atezolizumab, which are considered as potential antitumor drugs. It was found in clinical use that some patients obtained long‐term efficacy, but most of them developed drug resistance recurrence in the later stage. The high incidence of drug resistance (including primary and acquired drug resistance) still cannot be ignored, which limited its clinical application and became a new problem in this field. Due to tumor heterogeneity, current limited research shows that PD‐1 or PD‐L1 monoclonal antibody drug resistance may be related to the following factors: mutation of tumor antigen and antigen presentation process, multiple immune checkpoint interactions, immune microenvironment changes dynamically, activation of oncogenic pathways, gene mutation and epigenetic changes of key proteins in tumors, tumor competitive metabolism, and accumulation of metabolites, etc, mechanisms of resistance are complex. Therefore, it is the most urgent task to further elucidate the mechanism of immune checkpoint inhibitor resistance, discover multitumor universal biomarkers, and develop new target agents to improve the response rate of immunotherapy in patients. In this study, the mechanism of anti‐PD‐1/PD‐L1 drug resistance in tumors, the potential biomarkers for predicting PD‐1 acquired resistance, and the recent development of combination therapy were reviewed one by one. It is believed that, based on the complex mechanism of drug resistance, it is of no clinical significance to simply search for and regulate drug resistance targets, and it may even produce drug resistance again soon. It is speculated that according to the possible tumor characteristics, three types of treatment methods should be combined to change the tumor microenvironment ecology and eliminate various heterogeneous tumor subsets, so as to reduce tumor drug resistance and improve long‐term clinical efficacy.

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“…Real-time immunomonitoring of T-cell-mediated killing of cancer cells in CRISPR-edited isogenic cancer cell models engineered for single or combinational transcriptional interference and/or activation of metabolic genes in physiological-like tissue culture conditions [ 178 , 179 ] would be performed to rapidly infer dependencies on metabolic genes and networks of tumor cell responses to T-cells and/or ICIs. The preclinical uncovering of metabolically-driven immunosuppressive signatures might generate hypotheses for clinical validation not only in publicly available transcriptomic data from comprehensive genomic approaches [ 180 , 181 ], but also in longitudinal tumor samples of patients on immune checkpoint blockade ( Figure 7 ).…”

Section: Clinical and Molecular Monitoring Of Tumor Cell-intrinsicmentioning

confidence: 99%

Tumor Cell-Intrinsic Immunometabolism and Precision Nutrition in Cancer Immunotherapy

Cuyàs

Verdura

Martín-Castillo

et al. 2020

Cancers

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One of the greatest challenges in the cancer immunotherapy field is the need to biologically rationalize and broaden the clinical utility of immune checkpoint inhibitors (ICIs). The balance between metabolism and immune response has critical implications for overcoming the major weaknesses of ICIs, including their lack of universality and durability. The last decade has seen tremendous advances in understanding how the immune system’s ability to kill tumor cells requires the conspicuous metabolic specialization of T-cells. We have learned that cancer cell-associated metabolic activities trigger shifts in the abundance of some metabolites with immunosuppressory roles in the tumor microenvironment. Yet very little is known about the tumor cell-intrinsic metabolic traits that control the immune checkpoint contexture in cancer cells. Likewise, we lack a comprehensive understanding of how systemic metabolic perturbations in response to dietary interventions can reprogram the immune checkpoint landscape of tumor cells. We here review state-of-the-art molecular- and functional-level interrogation approaches to uncover how cell-autonomous metabolic traits and diet-mediated changes in nutrient availability and utilization might delineate new cancer cell-intrinsic metabolic dependencies of tumor immunogenicity. We propose that clinical monitoring and in-depth molecular evaluation of the cancer cell-intrinsic metabolic traits involved in primary, adaptive, and acquired resistance to cancer immunotherapy can provide the basis for improvements in therapeutic responses to ICIs. Overall, these approaches might guide the use of metabolic therapeutics and dietary approaches as novel strategies to broaden the spectrum of cancer patients and indications that can be effectively treated with ICI-based cancer immunotherapy.

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

Cited by 95 publications

References 54 publications

Recent advances in the role of sphingosine 1‐phosphate in cancer

Recent advances in the role of sphingosine 1‐phosphate in cancer

Study and analysis of antitumor resistance mechanism of PD1/PD‐L1 immune checkpoint blocker

Tumor Cell-Intrinsic Immunometabolism and Precision Nutrition in Cancer Immunotherapy

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