CDK4/6 Inhibitors Increase PD-L1 Expression

Immune checkpoint blockade achieves durable clinical responses in some patients with cancer; however, many patients fail to respond to anti–PD-1/anti–PD-L1 therapy. The underlying mechanisms of resistance are not well understood, but PD-L1 expression levels may be associated with response. Zhang, Bu, Wang, and colleagues found that PD-L1 expression fluctuates during the cell cycle, suggesting the potential for regulation by cyclin-dependent kinases (CDK). Consistent with this hypothesis, depletion of cyclin D increased PD-L1 levels in mouse embryonic fibroblasts. Similarly, depletion of the cyclin D catalytic partner CDK4 or treatment with selective CDK4/6 kinase inhibitors also increased PD-L1 levels. In vivo, CDK4/6 inhibition upregulated PD-L1 and reduced the number of CD3⁺ tumor-infiltrating lymphocytes (TIL) in mice with autochthonous breast cancer or allografts of colon cancer or melanoma. Futhermore, treating cells with a proteasome inhibitor or cullin-based ubiquitin E3 ligase inhibitor increase PD-L1 levels, suggesting that PD-L1 may be regulated by proteasomal degradation. Accordingly, the E3 ligase Cullin 3 interacted with the PD-L1 cytoplasmic domain via the SPOP substrate-recruiting adaptor protein, supporting a possible role for Cullin 3^SPOP as the physiologic E3 ubiquitin ligase for PD-L1 regulation. Consistent with this idea, SPOP deficiency was associated with increased PD-L1 expression and reduced TILs in primary human prostate cancer. Mechanistically, Cyclin D/CDK4 phosphorylated SPOP, leading to SPOP stabilization by recruiting 14-3-3γ to disrupt SPOP binding to CDH1, thereby reducing its polyubiquitination and degradation. The finding that CDK4/6 inhibitors increase PD-L1 expression suggested that the benefits of cell-cycle inhibition might be offset by increased immune evasion, raising the possibility of combining CDK4/6 inhibition with anti–PD-1/PD-L1. As predicted, CDK4/6 inhibition synergized with anti–PD-1 to restore TILs and suppress tumor growth in vivo. Collectively, these results elucidate a mechanism of PD-L1 regulation, and suggest that combining anti–PD-1/PD-L1 with CDK4/6 inhibitors may improve antitumor efficacy in patients with cancer.

Zhang J, Bu X, Wang H, Zhu Y, Geng Y, Nihira NT, et al. Cyclin D-CDK4 kinase destabilizes PD-L1 via Cul3SPOP to control cancer immune surveillance. Nature 2017 Nov 16 [Epub ahead of print].

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