MYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies

Srividya Swaminathan; Aida S. Hansen; Line D. Heftdal; Renumathy Dhanasekaran; Anja Deutzmann; Wadie D.M. Fernandez; Daniel F. Liefwalker; Crista Horton; Adriane Mosley; Mariola Liebersbach; Holden T. Maecker; Dean W. Felsher

doi:10.1038/s41467-020-16447-7

MYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies

Srividya Swaminathan, Aida S. Hansen, Line D. Heftdal, Renumathy Dhanasekaran, Anja Deutzmann, Wadie D.M. Fernandez, Daniel F. Liefwalker, Crista Horton, Adriane Mosley, Mariola Liebersbach, Holden T. Maecker, Dean W. Felsher

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17 Scopus citations

Abstract

The MYC oncogene drives T- and B- lymphoid malignancies, including Burkitt’s lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). Here, we demonstrate a systemic reduction in natural killer (NK) cell numbers in SRα-tTA/Tet-O-MYC^ON mice bearing MYC-driven T-lymphomas. Residual mNK cells in spleens of MYC^ON T-lymphoma-bearing mice exhibit perturbations in the terminal NK effector differentiation pathway. Lymphoma-intrinsic MYC arrests NK maturation by transcriptionally repressing STAT1/2 and secretion of Type I Interferons (IFNs). Treating T-lymphoma-bearing mice with Type I IFN improves survival by rescuing NK cell maturation. Adoptive transfer of mature NK cells is sufficient to delay both T-lymphoma growth and recurrence post MYC inactivation. In MYC-driven BL patients, low expression of both STAT1 and STAT2 correlates significantly with the absence of activated NK cells and predicts unfavorable clinical outcomes. Our studies thus provide a rationale for developing NK cell-based therapies to effectively treat MYC-driven lymphomas in the future.

Original language	English (US)
Article number	2860
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16447-7
State	Published - Dec 1 2020
Externally published	Yes

ASJC Scopus subject areas

General
Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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Swaminathan, S., Hansen, A. S., Heftdal, L. D., Dhanasekaran, R., Deutzmann, A., Fernandez, W. D. M., Liefwalker, D. F., Horton, C., Mosley, A., Liebersbach, M., Maecker, H. T., & Felsher, D. W. (2020). MYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies. Nature communications, 11(1), [2860]. https://doi.org/10.1038/s41467-020-16447-7

@article{53c8f97d359949e8baebb7aa96ddb80c,

title = "MYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies",

abstract = "The MYC oncogene drives T- and B- lymphoid malignancies, including Burkitt{\textquoteright}s lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). Here, we demonstrate a systemic reduction in natural killer (NK) cell numbers in SRα-tTA/Tet-O-MYCON mice bearing MYC-driven T-lymphomas. Residual mNK cells in spleens of MYCON T-lymphoma-bearing mice exhibit perturbations in the terminal NK effector differentiation pathway. Lymphoma-intrinsic MYC arrests NK maturation by transcriptionally repressing STAT1/2 and secretion of Type I Interferons (IFNs). Treating T-lymphoma-bearing mice with Type I IFN improves survival by rescuing NK cell maturation. Adoptive transfer of mature NK cells is sufficient to delay both T-lymphoma growth and recurrence post MYC inactivation. In MYC-driven BL patients, low expression of both STAT1 and STAT2 correlates significantly with the absence of activated NK cells and predicts unfavorable clinical outcomes. Our studies thus provide a rationale for developing NK cell-based therapies to effectively treat MYC-driven lymphomas in the future.",

author = "Srividya Swaminathan and Hansen, {Aida S.} and Heftdal, {Line D.} and Renumathy Dhanasekaran and Anja Deutzmann and Fernandez, {Wadie D.M.} and Liefwalker, {Daniel F.} and Crista Horton and Adriane Mosley and Mariola Liebersbach and Maecker, {Holden T.} and Felsher, {Dean W.}",

note = "Funding Information: We thank M. D. Leipold, R. Fernandez and Y. Rosenberg-Hasson at the Human Immune Monitoring Center, Stanford University for Luminex, CyTOF and Phospho-CyTOF acquisition. We also thank P. Chu in the Department of Pathology at Stanford University for carrying out tissue sectioning; H. Dai for technical help; A. Gentles for providing us access to PRECOG data sets; and M. Eilers for gifting us lentiviral overexpression plasmids for the study. We thank M. Eilers for his expert scientific guidance and suggestions. This work was supported by the following grants: NIH/NCI CA170378PQ2 (D.W.F.), 1U01CA188383-01/S1 (D.W.F.), Emerson Collective Cancer Research Fund (D.W.F.), the Special Fellow Award LLS 3366-17 from The Leukemia and Lymphoma Society (S.S.) and American Society of Hematology Scholar Award (S.S.). A.S.H. was funded by Grant 8026-00018B from Independent Research Fund Denmark, L.D.H. was funded by the Lundbeck Foundation, Denmark, R.D was funded by K08 National Cancer Institute (CA222676), and D.F.L. was supported by Tumor Biology Training Grant (NIH 5T32CA009151-38), Stanford University (National Cancer Institute), Burroughs Wellcome Fund Postdoctoral Enrichment Award and Research Supplement Award (National Cancer Institute). Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

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doi = "10.1038/s41467-020-16447-7",

language = "English (US)",

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T1 - MYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies

AU - Swaminathan, Srividya

AU - Hansen, Aida S.

AU - Heftdal, Line D.

AU - Dhanasekaran, Renumathy

AU - Deutzmann, Anja

AU - Fernandez, Wadie D.M.

AU - Liefwalker, Daniel F.

AU - Horton, Crista

AU - Mosley, Adriane

AU - Liebersbach, Mariola

AU - Maecker, Holden T.

AU - Felsher, Dean W.

N1 - Funding Information: We thank M. D. Leipold, R. Fernandez and Y. Rosenberg-Hasson at the Human Immune Monitoring Center, Stanford University for Luminex, CyTOF and Phospho-CyTOF acquisition. We also thank P. Chu in the Department of Pathology at Stanford University for carrying out tissue sectioning; H. Dai for technical help; A. Gentles for providing us access to PRECOG data sets; and M. Eilers for gifting us lentiviral overexpression plasmids for the study. We thank M. Eilers for his expert scientific guidance and suggestions. This work was supported by the following grants: NIH/NCI CA170378PQ2 (D.W.F.), 1U01CA188383-01/S1 (D.W.F.), Emerson Collective Cancer Research Fund (D.W.F.), the Special Fellow Award LLS 3366-17 from The Leukemia and Lymphoma Society (S.S.) and American Society of Hematology Scholar Award (S.S.). A.S.H. was funded by Grant 8026-00018B from Independent Research Fund Denmark, L.D.H. was funded by the Lundbeck Foundation, Denmark, R.D was funded by K08 National Cancer Institute (CA222676), and D.F.L. was supported by Tumor Biology Training Grant (NIH 5T32CA009151-38), Stanford University (National Cancer Institute), Burroughs Wellcome Fund Postdoctoral Enrichment Award and Research Supplement Award (National Cancer Institute). Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - The MYC oncogene drives T- and B- lymphoid malignancies, including Burkitt’s lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). Here, we demonstrate a systemic reduction in natural killer (NK) cell numbers in SRα-tTA/Tet-O-MYCON mice bearing MYC-driven T-lymphomas. Residual mNK cells in spleens of MYCON T-lymphoma-bearing mice exhibit perturbations in the terminal NK effector differentiation pathway. Lymphoma-intrinsic MYC arrests NK maturation by transcriptionally repressing STAT1/2 and secretion of Type I Interferons (IFNs). Treating T-lymphoma-bearing mice with Type I IFN improves survival by rescuing NK cell maturation. Adoptive transfer of mature NK cells is sufficient to delay both T-lymphoma growth and recurrence post MYC inactivation. In MYC-driven BL patients, low expression of both STAT1 and STAT2 correlates significantly with the absence of activated NK cells and predicts unfavorable clinical outcomes. Our studies thus provide a rationale for developing NK cell-based therapies to effectively treat MYC-driven lymphomas in the future.

AB - The MYC oncogene drives T- and B- lymphoid malignancies, including Burkitt’s lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). Here, we demonstrate a systemic reduction in natural killer (NK) cell numbers in SRα-tTA/Tet-O-MYCON mice bearing MYC-driven T-lymphomas. Residual mNK cells in spleens of MYCON T-lymphoma-bearing mice exhibit perturbations in the terminal NK effector differentiation pathway. Lymphoma-intrinsic MYC arrests NK maturation by transcriptionally repressing STAT1/2 and secretion of Type I Interferons (IFNs). Treating T-lymphoma-bearing mice with Type I IFN improves survival by rescuing NK cell maturation. Adoptive transfer of mature NK cells is sufficient to delay both T-lymphoma growth and recurrence post MYC inactivation. In MYC-driven BL patients, low expression of both STAT1 and STAT2 correlates significantly with the absence of activated NK cells and predicts unfavorable clinical outcomes. Our studies thus provide a rationale for developing NK cell-based therapies to effectively treat MYC-driven lymphomas in the future.

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MYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies

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