MYC regulates the antitumor immune response through CD47 and PD-L1

Stephanie C. Casey; Ling Tong; Yulin Li; Rachel Do; Susanne Walz; Kelly N. Fitzgerald; Arvin M. Gouw; Virginie Baylot; Ines Gütgemann; Martin Eilers; Dean W. Felsher

doi:10.1126/science.aac9935

MYC regulates the antitumor immune response through CD47 and PD-L1

Stephanie C. Casey, Ling Tong, Yulin Li, Rachel Do, Susanne Walz, Kelly N. Fitzgerald, Arvin M. Gouw, Virginie Baylot, Ines Gütgemann, Martin Eilers, Dean W. Felsher

Research output: Contribution to journal › Article › peer-review

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Abstract

The MYC oncogene codes for a transcription factor that is overexpressed in many human cancers. Here we show that MYC regulates the expression of two immune checkpoint proteins on the tumor cell surface: the innate immune regulator CD47 (cluster of differentiation 47) and the adaptive immune checkpoint PD-L1 (programmed death-ligand 1). Suppression of MYC in mouse tumors and human tumor cells caused a reduction in the levels of CD47 and PD-L1 messenger RNA and protein. MYC was found to bind directly to the promoters of the Cd47 and Pd-11 genes. MYC inactivation in mouse tumors down-regulated CD47 and PD-L1 expression and enhanced the antitumor immune response. In contrast, when MYC was inactivated in tumors with enforced expression of CD47 or PD-L1, the immune response was suppressed, and tumors continued to grow. Thus, MYC appears to initiate and maintain tumorigenesis, in part, through the modulation of immune regulatory molecules.

Original language	English (US)
Pages (from-to)	227-231
Number of pages	5
Journal	Science
Volume	352
Issue number	6282
DOIs	https://doi.org/10.1126/science.aac9935
State	Published - Apr 8 2016

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@article{b5d2b835bf124c21b4e726dbb6409c43,

title = "MYC regulates the antitumor immune response through CD47 and PD-L1",

abstract = "The MYC oncogene codes for a transcription factor that is overexpressed in many human cancers. Here we show that MYC regulates the expression of two immune checkpoint proteins on the tumor cell surface: the innate immune regulator CD47 (cluster of differentiation 47) and the adaptive immune checkpoint PD-L1 (programmed death-ligand 1). Suppression of MYC in mouse tumors and human tumor cells caused a reduction in the levels of CD47 and PD-L1 messenger RNA and protein. MYC was found to bind directly to the promoters of the Cd47 and Pd-11 genes. MYC inactivation in mouse tumors down-regulated CD47 and PD-L1 expression and enhanced the antitumor immune response. In contrast, when MYC was inactivated in tumors with enforced expression of CD47 or PD-L1, the immune response was suppressed, and tumors continued to grow. Thus, MYC appears to initiate and maintain tumorigenesis, in part, through the modulation of immune regulatory molecules.",

author = "Casey, \{Stephanie C.\} and Ling Tong and Yulin Li and Rachel Do and Susanne Walz and Fitzgerald, \{Kelly N.\} and Gouw, \{Arvin M.\} and Virginie Baylot and Ines G{\"u}tgemann and Martin Eilers and Felsher, \{Dean W.\}",

note = "Funding Information: We thank E. Shroff, A. Deutzmann, J. Braun, D. Fruman, I. Weissman, and P. Betancur for helpful advice; P. Chu for pathology; N. Lacayo and G. Dahl for deidentified clinical specimens; C. Dang for nuclear run-on data sets; and the Small Animal Imaging Facility at the Stanford Center for Innovation in In-Vivo Imaging (SCI3). This work was supported by NIH R01 grants CA 089305, CA 170378, CA 184384, U01 CA 188383, and U01 CA 114747 and a Cancer Research Institute Clinic and Laboratory Innovation Program grant (D.W.F). S.C.C. was supported by NIH fellowships 1F32CA177139 and 5T32AI07290. K.N.F. was supported by a grant from Alex's Lemonade Stand Foundation. M.E. and S.W. were supported by Deutsche Forschungsgemeinschaft (DFG) grant Ei222/12-1 (to M.E.) and by the Deutsche Krebshilfe via the Comprehensive Cancer Center Mainfranken. I.G. was supported by DFG grant GU 1046/2-1. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. All data are stored at the Division of Oncology, Department of Medicine, Stanford University School of Medicine.",

year = "2016",

month = apr,

day = "8",

doi = "10.1126/science.aac9935",

language = "English (US)",

volume = "352",

pages = "227--231",

journal = "Science",

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T1 - MYC regulates the antitumor immune response through CD47 and PD-L1

AU - Casey, Stephanie C.

AU - Tong, Ling

AU - Li, Yulin

AU - Do, Rachel

AU - Walz, Susanne

AU - Fitzgerald, Kelly N.

AU - Gouw, Arvin M.

AU - Baylot, Virginie

AU - Gütgemann, Ines

AU - Eilers, Martin

AU - Felsher, Dean W.

N1 - Funding Information: We thank E. Shroff, A. Deutzmann, J. Braun, D. Fruman, I. Weissman, and P. Betancur for helpful advice; P. Chu for pathology; N. Lacayo and G. Dahl for deidentified clinical specimens; C. Dang for nuclear run-on data sets; and the Small Animal Imaging Facility at the Stanford Center for Innovation in In-Vivo Imaging (SCI3). This work was supported by NIH R01 grants CA 089305, CA 170378, CA 184384, U01 CA 188383, and U01 CA 114747 and a Cancer Research Institute Clinic and Laboratory Innovation Program grant (D.W.F). S.C.C. was supported by NIH fellowships 1F32CA177139 and 5T32AI07290. K.N.F. was supported by a grant from Alex's Lemonade Stand Foundation. M.E. and S.W. were supported by Deutsche Forschungsgemeinschaft (DFG) grant Ei222/12-1 (to M.E.) and by the Deutsche Krebshilfe via the Comprehensive Cancer Center Mainfranken. I.G. was supported by DFG grant GU 1046/2-1. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. All data are stored at the Division of Oncology, Department of Medicine, Stanford University School of Medicine.

PY - 2016/4/8

Y1 - 2016/4/8

N2 - The MYC oncogene codes for a transcription factor that is overexpressed in many human cancers. Here we show that MYC regulates the expression of two immune checkpoint proteins on the tumor cell surface: the innate immune regulator CD47 (cluster of differentiation 47) and the adaptive immune checkpoint PD-L1 (programmed death-ligand 1). Suppression of MYC in mouse tumors and human tumor cells caused a reduction in the levels of CD47 and PD-L1 messenger RNA and protein. MYC was found to bind directly to the promoters of the Cd47 and Pd-11 genes. MYC inactivation in mouse tumors down-regulated CD47 and PD-L1 expression and enhanced the antitumor immune response. In contrast, when MYC was inactivated in tumors with enforced expression of CD47 or PD-L1, the immune response was suppressed, and tumors continued to grow. Thus, MYC appears to initiate and maintain tumorigenesis, in part, through the modulation of immune regulatory molecules.

AB - The MYC oncogene codes for a transcription factor that is overexpressed in many human cancers. Here we show that MYC regulates the expression of two immune checkpoint proteins on the tumor cell surface: the innate immune regulator CD47 (cluster of differentiation 47) and the adaptive immune checkpoint PD-L1 (programmed death-ligand 1). Suppression of MYC in mouse tumors and human tumor cells caused a reduction in the levels of CD47 and PD-L1 messenger RNA and protein. MYC was found to bind directly to the promoters of the Cd47 and Pd-11 genes. MYC inactivation in mouse tumors down-regulated CD47 and PD-L1 expression and enhanced the antitumor immune response. In contrast, when MYC was inactivated in tumors with enforced expression of CD47 or PD-L1, the immune response was suppressed, and tumors continued to grow. Thus, MYC appears to initiate and maintain tumorigenesis, in part, through the modulation of immune regulatory molecules.

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SN - 0036-8075

VL - 352

SP - 227

EP - 231

JO - Science

JF - Science

IS - 6282

ER -

MYC regulates the antitumor immune response through CD47 and PD-L1

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