MYC Promotes Tumorigenesis via Activation of CD47 and PD-L1

Activation of the oncogenic MYC transcription factor has been observed in a variety of cancers and is known to drive tumor initiation and maintenance in murine cancer models. Complete tumor clearance in mice following MYC suppression requires a host-dependent immune response, but the mechanism by which MYC triggers this response is unknown. To determine how MYC modulates antitumor immune responses, Casey and colleagues used a Tet-off murine model of MYC-dependent T-cell acute lymphoblastic leukemia (T-ALL). While MYC was expressed, Cluster of Differentiation 47 (CD47), an innate and adaptive immune regulator, and programmed death-ligand 1 (PD-L1), an immune checkpoint protein, were both expressed. However, suppression of MYC through the addition of tetracycline led to the rapid downregulation of CD47 and PD-L1 both in vitro and in vivo. In line with these findings, MYC knockdown or inhibition with the bromodomain inhibitor JQ1 in human T-ALL cells led to a similar reduction in CD47 and PD-L1 expression. MYC was also shown to regulate PD-L1 and CD47 in human melanoma, kidney, and liver tumor–derived cell lines. Chromatin immunoprecipitation sequencing analysis indicated that MYC directly regulates CD47 and PD-L1 at the transcriptional level by binding to their promoters. Further, suppression of CD47 and PD-L1 was required for immune-mediated tumor clearance following MYC inactivation, as forced expression of CD47 or PD-L1 in T-ALL cells following MYC inactivation prevented tumor regression by reducing the recruitment of T cells and macrophages to the tumor, maintaining angiogenesis, and blocking the induction of senescence. Together, these results suggest that MYC-mediated inhibition of innate and adaptive antitumor responses via activation of CD47 and PD-L1 contributes to tumor maintenance, and indicates that reactivation of antitumor immune responses, by either suppression of MYC or immune checkpoint blockade, may have a clinical benefit in cancer cells that overexpress MYC.

Casey SC, Tong L, Li Y, Do R, Walz S, Fitzgerald KN, et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science 2016;352:227–31.

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