Natural Killer Cell Activation by Ubiquitin-specific Protease 6 Mediates Tumor Suppression in Ewing Sarcoma

Overview

Journal Cancer Res Commun

Specialty Oncology

Date 2023 Aug 24

PMID 37615015

Authors

Kanika Jain

Ian C Henrich

Laura Quick

Robert Young

Shreya Mondal

Andre M Oliveira

Gerd A Blobel

Margaret M Chou

Affiliations

Soon will be listed here.

Abstract

Significance: This study provides novel insights into the immunomodulatory functions of USP6, the only cancer cell-intrinsic factor demonstrated to regulate the immune TME in Ewing sarcoma. We demonstrate that USP6-mediated suppression of Ewing sarcoma tumorigenesis is dependent on NK cells. USP6 directly activates NK cell cytolytic function, inducing both intratumoral and systemic activation of NK cells in an Ewing sarcoma xenograft model.

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References

Robertson M . Role of chemokines in the biology of natural killer cells. J Leukoc Biol. 2002; 71(2):173-83. View

Henrich I, Young R, Quick L, Oliveira A, Chou M . USP6 Confers Sensitivity to IFN-Mediated Apoptosis through Modulation of TRAIL Signaling in Ewing Sarcoma. Mol Cancer Res. 2018; 16(12):1834-1843. PMC: 6279478. DOI: 10.1158/1541-7786.MCR-18-0289. View

Cho D, Shook D, Shimasaki N, Chang Y, Fujisaki H, Campana D . Cytotoxicity of activated natural killer cells against pediatric solid tumors. Clin Cancer Res. 2010; 16(15):3901-9. PMC: 3168562. DOI: 10.1158/1078-0432.CCR-10-0735. View

Evdokimova V, Gassmann H, Radvanyi L, Burdach S . Current State of Immunotherapy and Mechanisms of Immune Evasion in Ewing Sarcoma and Osteosarcoma. Cancers (Basel). 2023; 15(1). PMC: 9818129. DOI: 10.3390/cancers15010272. View

Kimpo M, Oh B, Lee S . The Role of Natural Killer Cells as a Platform for Immunotherapy in Pediatric Cancers. Curr Oncol Rep. 2019; 21(10):93. PMC: 6733832. DOI: 10.1007/s11912-019-0837-8. View

Urlaub D, Hofer K, Muller M, Watzl C . LFA-1 Activation in NK Cells and Their Subsets: Influence of Receptors, Maturation, and Cytokine Stimulation. J Immunol. 2017; 198(5):1944-1951. DOI: 10.4049/jimmunol.1601004. View

Quick L, Young R, Henrich I, Wang X, Asmann Y, Oliveira A . Jak1-STAT3 Signals Are Essential Effectors of the USP6/TRE17 Oncogene in Tumorigenesis. Cancer Res. 2016; 76(18):5337-47. PMC: 5026615. DOI: 10.1158/0008-5472.CAN-15-2391. View

Rossig C . Cellular immunotherapy strategies for Ewing sarcoma. Immunotherapy. 2014; 6(5):611-21. DOI: 10.2217/imt.14.36. View

Zhang C, Oberoi P, Oelsner S, Waldmann A, Lindner A, Tonn T . Chimeric Antigen Receptor-Engineered NK-92 Cells: An Off-the-Shelf Cellular Therapeutic for Targeted Elimination of Cancer Cells and Induction of Protective Antitumor Immunity. Front Immunol. 2017; 8:533. PMC: 5435757. DOI: 10.3389/fimmu.2017.00533. View

10.

Cassetta L, Pollard J . Cancer immunosurveillance: role of patrolling monocytes. Cell Res. 2015; 26(1):3-4. PMC: 4816132. DOI: 10.1038/cr.2015.144. View

11.

Berghuis D, Santos S, Baelde H, Taminiau A, Egeler R, Schilham M . Pro-inflammatory chemokine-chemokine receptor interactions within the Ewing sarcoma microenvironment determine CD8(+) T-lymphocyte infiltration and affect tumour progression. J Pathol. 2010; 223(3):347-57. DOI: 10.1002/path.2819. View

12.

Zamai L, Ponti C, Mirandola P, Gobbi G, Papa S, Galeotti L . NK cells and cancer. J Immunol. 2007; 178(7):4011-6. DOI: 10.4049/jimmunol.178.7.4011. View

13.

Hayakawa Y, Smyth M . CD27 dissects mature NK cells into two subsets with distinct responsiveness and migratory capacity. J Immunol. 2006; 176(3):1517-24. DOI: 10.4049/jimmunol.176.3.1517. View

14.

Berghuis D, de Hooge A, Santos S, Horst D, Wiertz E, van Eggermond M . Reduced human leukocyte antigen expression in advanced-stage Ewing sarcoma: implications for immune recognition. J Pathol. 2009; 218(2):222-31. DOI: 10.1002/path.2537. View

15.

Morales E, Olson M, Iglesias F, Dahiya S, Luetkens T, Atanackovic D . Role of immunotherapy in Ewing sarcoma. J Immunother Cancer. 2020; 8(2). PMC: 7725096. DOI: 10.1136/jitc-2020-000653. View

16.

Gangwal K, Sankar S, Hollenhorst P, Kinsey M, Haroldsen S, Shah A . Microsatellites as EWS/FLI response elements in Ewing's sarcoma. Proc Natl Acad Sci U S A. 2008; 105(29):10149-54. PMC: 2481306. DOI: 10.1073/pnas.0801073105. View

17.

Lessnick S, Ladanyi M . Molecular pathogenesis of Ewing sarcoma: new therapeutic and transcriptional targets. Annu Rev Pathol. 2011; 7:145-59. PMC: 3555146. DOI: 10.1146/annurev-pathol-011110-130237. View

18.

Riggi N, Knoechel B, Gillespie S, Rheinbay E, Boulay G, Suva M . EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma. Cancer Cell. 2014; 26(5):668-681. PMC: 4492343. DOI: 10.1016/j.ccell.2014.10.004. View

19.

Peng Y, Luo G, Zhou J, Wang X, Hu J, Cui Y . CD86 is an activation receptor for NK cell cytotoxicity against tumor cells. PLoS One. 2013; 8(12):e83913. PMC: 3859666. DOI: 10.1371/journal.pone.0083913. View

20.

Henrich I, Jain K, Young R, Quick L, Lindsay J, Park D . Ubiquitin-Specific Protease 6 Functions as a Tumor Suppressor in Ewing Sarcoma through Immune Activation. Cancer Res. 2021; 81(8):2171-2183. PMC: 8137534. DOI: 10.1158/0008-5472.CAN-20-1458. View