MYC Regulates the Anti-Tumor Immune Response through CD47 and PD-L1
By S. Casey, Ling Tong, Yulin Li, R. Do, S. Walz, Kelly N Fitzgerald, A. Gouw, V. Baylot, I. Gutgemann, M. Eilers and 1 more. Science, 2016
1,260 citations recorded by the source corpus.
Oncogene control of antitumor immunity Recent clinical success of cancer immunotherapy has intensified interest in how tumors normally evade the immune response. Whether and how oncogenes contribute to this process are not well understood. In a study of mice, Casey et al. found that the MYC oncogene, which is aberrantly activated in many human cancers, up-regulates the expression of genes encoding proteins that dampen the antitumor response. These include two proteins that are often overexpressed on tumor cells and that serve as immune checkpoints. One of them (PDL1) sends to the immune system a “don't find me” signal, and the other (CD47) sends a “don't eat me” signal. Thus, therapies aimed at suppressing MYC may help promote an immune response against tumors. Science, this issue p. 227 Aberrant activation of the MYC gene helps tumor cells evade the immune response. 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-l1 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.
Subfields: Immunology, Oncology
View Paper: https://www.semanticscholar.org/paper/0a1c350b441937b2bf3d2f00a6e64d47cb3bcb73
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Citations in the corpus
- Diversity, Mechanisms and Significance of Macrophage Plasticity (2019, background): “C-myc, an oncogene involved in many cancers, amplifies CD47 and PD-L1 (160).”
- Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory (2019, neutral): “Pd-l1 qPCR forward primer: GGCATTTGCTGAACGCAT, Pd-l1 qPCR reverse primer: CAATTAGTGCAGCCAGGT (Casey et al., 2016).”
- Mechanisms controlling PD-L1 expression in cancer (2019, background): “By harnessing the IFN-γ/JAK/STAT1 pathway, PDL1 expressed on cancer cells inactivate cytotoxic T cells and attenuate immunosurveillance in the TME.”
- Cyclin D-CDK4 kinase destabilizes PD-L1 via Cul3SPOP to control cancer immune surveillance (2017, positive): “Although it has been reported that PD-L1 expression can be regulated at both transcriptional 9,10 and post-translational levels 11,12 , it remains unclear whether PD-L1 stability is regulated under physiological conditions such as during cell cycle progression.”
- Genetics and biology of prostate cancer (2018, background): “In addition, activation of the MYC, WNT, and MAPK pathways (Spranger et al. 2015; Casey et al. 2016) and loss of PTEN (Peng et al. 2016) have been implicated in primary and adaptive resistance inmelanoma and T-lineage acute lymphoblastic leukemia.”
- Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy (2022, background): “As well as PD-1/PD-L1, CTLA4, and IDO, SIRPα/CD47 immune checkpoints act as “don’t eat me” signals to prevent macrophage phagocytosis of cancer cells.(204,205) CD47, which is highly expressed on cancer cells, binds to SIRPα on macrophages, inhibiting phagocytosis.”