Cancer Immunol Res. 2021 May;9(5):568-582. doi: 10.1158/2326-6066.CIR-20-0342. Epub 2021 Mar 16.

Neutral Sphingomyelinase 2 Heightens Anti-Melanoma Immune Responses and Anti-PD-1 Therapy Efficacy.

Cancer immunology research

Anne Montfort, Florie Bertrand, Julia Rochotte, Julia Gilhodes, Thomas Filleron, Jean Milhès, Carine Dufau, Caroline Imbert, Joëlle Riond, Marie Tosolini, Christopher J Clarke, Florent Dufour, Andrei A Constantinescu, Nilton De França Junior, Virginie Garcia, Michel Record, Pierre Cordelier, Pierre Brousset, Philippe Rochaix, Sandrine Silvente-Poirot, Nicole Therville, Nathalie Andrieu-Abadie, Thierry Levade, Yusuf A Hannun, Hervé Benoist, Nicolas Meyer, Olivier Micheau, Céline Colacios, Bruno Ségui

PMID: 33727246 DOI: 10.1158/2326-6066.CIR-20-0342

Abstract

Dysregulation of lipid metabolism affects the behavior of cancer cells, but how this happens is not completely understood. Neutral sphingomyelinase 2 (nSMase2), encoded by

©2021 American Association for Cancer Research.

References

1. Ogretmen B. Sphingolipid metabolism in cancer signalling and therapy. Nat Rev Cancer. 2018;18:33–50. - PubMed
2. Hannun YA. The sphingomyelin cycle and the second messenger function of ceramide. J Biol Chem. 1994;269:3125–8. - PubMed
3. Milhas D, Clarke CJ, Hannun YA. Sphingomyelin metabolism at the plasma membrane: implications for bioactive sphingolipids. FEBS Lett. 2010;584:1887–94. - PubMed
4. Hofmann K, Tomiuk S, Wolff G, Stoffel W. Cloning and characterization of the mammalian brain-specific, Mg2+-dependent neutral sphingomyelinase. Proc Natl Acad Sci U S A. 2000;97:5895–900. - PubMed
5. Rutkute K, Karakashian AA, Giltiay NV, Dobierzewska A, Nikolova-Karakashian MN. Aging in rat causes hepatic hyperresposiveness to interleukin-1beta which is mediated by neutral sphingomyelinase-2. Hepatology. 2007;46:1166–76. - PubMed
6. Clarke CJ, Truong TG, Hannun YA. Role for neutral sphingomyelinase-2 in tumor necrosis factor alpha-stimulated expression of vascular cell adhesion molecule-1 (VCAM) and intercellular adhesion molecule-1 (ICAM) in lung epithelial cells: p38 MAPK is an upstream regulator of nSMase2. J Biol Chem. 2007;282:1384–96. - PubMed
7. Shamseddine AA, Clarke CJ, Carroll B, Airola MV, Mohammed S, Rella A, et al. P53-dependent upregulation of neutral sphingomyelinase-2: role in doxorubicin-induced growth arrest. Cell Death Dis. 2015;6:e1947. - PubMed
8. Kim WJ, Okimoto RA, Purton LE, Goodwin M, Haserlat SM, Dayyani F, et al. Mutations in the neutral sphingomyelinase gene SMPD3 implicate the ceramide pathway in human leukemias. Blood. 2008;111:4716–22. - PubMed
9. Demircan B, Dyer LM, Gerace M, Lobenhofer EK, Robertson KD, Brown KD. Comparative epigenomics of human and mouse mammary tumors. Genes Chromosomes Cancer. 2009;48:83–97. - PubMed
10. Albinet V, Bats ML, Huwiler A, Rochaix P, Chevreau C, Segui B, et al. Dual role of sphingosine kinase-1 in promoting the differentiation of dermal fibroblasts and the dissemination of melanoma cells. Oncogene. 2014;33:3364–73. - PubMed
11. Sorli SC, Colie S, Albinet V, Dubrac A, Touriol C, Guilbaud N, et al. The nonlysosomal beta-glucosidase GBA2 promotes endoplasmic reticulum stress and impairs tumorigenicity of human melanoma cells. FASEB J. 2013;27:489–98. - PubMed
12. Bedia C, Casas J, Andrieu-Abadie N, Fabrias G, Levade T. Acid ceramidase expression modulates the sensitivity of A375 melanoma cells to dacarbazine. J Biol Chem. 2011;286:28200–9. - PubMed
13. Colie S, Van Veldhoven PP, Kedjouar B, Bedia C, Albinet V, Sorli SC, et al. Disruption of sphingosine 1-phosphate lyase confers resistance to chemotherapy and promotes oncogenesis through Bcl-2/Bcl-xL upregulation. Cancer Res. 2009;69:9346–53. - PubMed
14. Bilal F, Montfort A, Gilhodes J, Garcia V, Riond J, Carpentier S, et al. Sphingomyelin synthase 1 (SMS1) downregulation is associated with sphingolipid reprogramming and a worse prognosis in melanoma. Front Pharmacol. 2019;10:443. - PubMed
15. Imbert C, Montfort A, Fraisse M, Marcheteau E, Gilhodes J, Martin E, et al. Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1. Nat Commun. 2020;11:437. - PubMed
16. Mrad M, Imbert C, Garcia V, Rambow F, Therville N, Carpentier S, et al. Downregulation of sphingosine kinase-1 induces protective tumor immunity by promoting M1 macrophage response in melanoma. Oncotarget. 2016;7:71873–86. - PubMed
17. Garandeau D, Noujarede J, Leclerc J, Imbert C, Garcia V, Bats ML, et al. Targeting the sphingosine 1-phosphate axis exerts potent antitumor activity in BRAFi-resistant melanomas. Mol Cancer Ther. 2019;18:289–300. - PubMed
18. Belleri M, Paganini G, Coltrini D, Ronca R, Zizioli D, Corsini M, et al. Beta-galactosylceramidase promotes melanoma growth via modulation of ceramide metabolism. Cancer Res. 2020;80:5011–23. - PubMed
19. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34. - PubMed
20. Riker AI, Enkemann SA, Fodstad O, Liu S, Ren S, Morris C, et al. The gene expression profiles of primary and metastatic melanoma yields a transition point of tumor progression and metastasis. BMC Med Genomics. 2008;1:13. - PubMed
21. Genomic classification of cutaneous melanoma. Cell. 2015;161:1681–96. - PubMed
22. Ycart B, Pont F, Fournie JJ. Curbing false discovery rates in interpretation of genome-wide expression profiles. J Biomed Inform. 2014;47:58–61. - PubMed
23. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102:15545–50. - PubMed
24. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1. - PubMed
25. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio Cancer Genomics Portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4. - PubMed
26. Bertrand F, Rochotte J, Colacios C, Montfort A, Tilkin-Mariame AF, Touriol C, et al. Blocking tumor necrosis factor alpha enhances CD8 T-cell-dependent immunity in experimental melanoma. Cancer Res. 2015;75:2619–28. - PubMed
27. Porgador A, Feldman M, Eisenbach L. H-2Kb transfection of B16 melanoma cells results in reduced tumourigenicity and metastatic competence. J Immunogenet. 1989;16:291–303. - PubMed
28. Meeth K, Wang JX, Micevic G, Damsky W, Bosenberg MW. The YUMM lines: a series of congenic mouse melanoma cell lines with defined genetic alterations. Pigment Cell Melanoma Res. 2016;29:590–7. - PubMed
29. Pencheva N, Buss CG, Posada J, Merghoub T, Tavazoie SF. Broad-spectrum therapeutic suppression of metastatic melanoma through nuclear hormone receptor activation. Cell. 2014;156:986–1001. - PubMed
30. Tani M, Hannun YA. Analysis of membrane topology of neutral sphingomyelinase 2. FEBS Lett. 2007;581:1323–8. - PubMed
31. Subra C, Grand D, Laulagnier K, Stella A, Lambeau G, Paillasse M, et al. Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins. J Lipid Res. 2010;51:2105–20. - PubMed
32. Micheau O, Lens S, Gaide O, Alevizopoulos K, Tschopp J. NF-kappaB signals induce the expression of c-FLIP. Mol Cell Biol. 2001;21:5299–305. - PubMed
33. Morgenstern JP, Land H. Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. Nucleic Acids Res. 1990;18:3587–96. - PubMed
34. Wiegmann K, Schutze S, Machleidt T, Witte D, Kronke M. Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling. Cell. 1994;78:1005–15. - PubMed
35. Bielawski J, Szulc ZM, Hannun YA, Bielawska A. Simultaneous quantitative analysis of bioactive sphingolipids by high-performance liquid chromatography-tandem mass spectrometry. Methods. 2006;39:82–91. - PubMed
36. Bertrand F, Montfort A, Marcheteau E, Imbert C, Gilhodes J, Filleron T, et al. TNFalpha blockade overcomes resistance to anti-PD-1 in experimental melanoma. Nat Commun. 2017;8:2256. - PubMed
37. Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, et al. A landscape of driver mutations in melanoma. Cell. 2012;150:251–63. - PubMed
38. Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, McCusker JP, et al. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet. 2012;44:1006–14. - PubMed
39. Shain AH, Garrido M, Botton T, Talevich E, Yeh I, Sanborn JZ, et al. Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway. Nat Genet. 2015;47:1194–9. - PubMed
40. Hoadley KA, Yau C, Hinoue T, Wolf DM, Lazar AJ, Drill E, et al. Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell. 2018;173:291–304. - PubMed
41. Airola MV, Shanbhogue P, Shamseddine AA, Guja KE, Senkal CE, Maini R, et al. Structure of human nSMase2 reveals an interdomain allosteric activation mechanism for ceramide generation. Proc Natl Acad Sci U S A. 2017;114:E5549–E58. - PubMed
42. Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science. 2008;319:1244–7. - PubMed
43. Andre F, Schartz NE, Movassagh M, Flament C, Pautier P, Morice P, et al. Malignant effusions and immunogenic tumour-derived exosomes. Lancet. 2002;360:295–305. - PubMed
44. Chen G, Huang AC, Zhang W, Zhang G, Wu M, Xu W, et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature. 2018;560:382–6. - PubMed
45. Poggio M, Hu T, Pai CC, Chu B, Belair CD, Chang A, et al. Suppression of exosomal PD-L1 induces systemic anti-tumor immunity and memory. Cell. 2019;177:414–27. - PubMed
46. Lim SO, Li CW, Xia W, Cha JH, Chan LC, Wu Y, et al. Deubiquitination and stabilization of PD-L1 by CSN5. Cancer Cell. 2016;30:925–39. - PubMed
47. Eppihimer MJ, Gunn J, Freeman GJ, Greenfield EA, Chernova T, Erickson J, et al. Expression and regulation of the PD-L1 immunoinhibitory molecule on microvascular endothelial cells. Microcirculation. 2002;9:133–45. - PubMed
48. Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol. 2008;9:139–50. - PubMed
49. Garcia-Barros M, Paris F, Cordon-Cardo C, Lyden D, Rafii S, Haimovitz-Friedman A, et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science. 2003;300:1155–9. - PubMed
50. Garcia-Barros M, Lacorazza D, Petrie H, Haimovitz-Friedman A, Cardon-Cardo C, Nimer S, et al. Host acid sphingomyelinase regulates microvascular function not tumor immunity. Cancer Res. 2004;64:8285–91. - PubMed
51. Carpinteiro A, Becker KA, Japtok L, Hessler G, Keitsch S, Pozgajova M, et al. Regulation of hematogenous tumor metastasis by acid sphingomyelinase. EMBO Mol Med. 2015;7:714–34. - PubMed
52. Bizzozero L, Cazzato D, Cervia D, Assi E, Simbari F, Pagni F, et al. Acid sphingomyelinase determines melanoma progression and metastatic behaviour via the microphtalmia-associated transcription factor signalling pathway. Cell Death Differ. 2014;21:507–20. - PubMed
53. Assi E, Cervia D, Bizzozero L, Capobianco A, Pambianco S, Morisi F, et al. Modulation of acid sphingomyelinase in melanoma reprogrammes the tumour immune microenvironment. Mediators Inflamm. 2015;2015:370482. - PubMed
54. Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, Brinkmann V, et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature. 2004;427:355–60. - PubMed
55. Joseph CK, Wright SD, Bornmann WG, Randolph JT, Kumar ER, Bittman R, et al. Bacterial lipopolysaccharide has structural similarity to ceramide and stimulates ceramide-activated protein kinase in myeloid cells. J Biol Chem. 1994;269:17606–10. - PubMed
56. Li G, Liu D, Kimchi ET, Kaifi JT, Qi X, Manjunath Y, et al. Nanoliposome C6-ceramide increases the anti-tumor immune response and slows growth of liver tumors in mice. Gastroenterology. 2018;154:1024–36. - PubMed
57. Zhang T, de Waard AA, Wuhrer M, Spaapen RM. The role of glycosphingolipids in immune cell functions. Front Immunol. 2019;10:90. - PubMed

Publication Types

• Journal Article
• Research Support, Non-U.S. Gov't

Grant support

• P01 CA097132/CA/NCI NIH HHS/United States
• R35 GM118128/GM/NIGMS NIH HHS/United States