HuR up-regulates cell surface PD-L1 via stabilizing CMTM6 transcript in cancer

Yanbin Liu,Xingzhi Li,Yanli Wei,Mingming Zhang,Hui Zhang

doi:10.1038/s41388-021-01689-6

Yanbin Liu, Xingzhi Li + Show 3 more

Open Access

https://doi.org/10.1038/s41388-021-01689-6

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Abstract

Despite the well-established role of CMTM6 in the stabilization of cell surface PD-L1 in cancer cells, the mechanisms underlying CMTM6 expression and regulation are still largely unknown. Here we unexpectedly find a strikingly positive correlation between CMTM6 and Hu-Antigen R (HuR) expression in most types of cancer. Mechanistically, we elucidate HuR stabilizes CMTM6 mRNA via direct association with AU-rich elements (AREs) in its 3′UTR and predominantly up-regulates CMTM6, which is readily abolished by HuR-specific inhibitor, MS-444. Phenotypically, we notice abundant cell surface PD-L1 in HuR-high cancer cells, which significantly inhibits immune activation of co-cultured T cells as indicated by IL-2 production. Treatment with MS-444 completely relieves immune suppression imposed by HuR-overexpression and further stimulates immune responses. Ectopic HuR accelerates allograft tumor progression in vivo, which is greatly compromised by simultaneous administration with MS-444. Our study uncovers a novel mechanism in control of CMTM6 and therefore PD-L1 expression, and suggests the potential of combining HuR inhibitor with PD-1/PD-L1 antibodies for cancer immunotherapy.

Highlights

Immunotherapies targeting immune checkpoints, such as PD-L1, have achieved unprecedented clinical success in a number of human cancers [1], which highlights the importance of understanding the molecular mechanisms underlying PD-L1 regulation [2]
Quantitative PCR results demonstrated that CMTM6 transcripts were significantly up-regulated in Hu-Antigen R (HuR)-proficient 786–0 cells in comparison with empty vector control, while downregulated in HuR-deficient ACHN cells compared to scrambled control (Fig. 1F)
There were no significant differences in both HuR and CMTM6 expressions between normal and tumor tissues, which may suggest that HuR-CMTM6 is aberrantly high in a subpopulation of clear cell renal cell carcinoma (ccRCC) (Fig. S3)

Summary

Introduction

Immunotherapies targeting immune checkpoints, such as PD-L1, have achieved unprecedented clinical success in a number of human cancers [1], which highlights the importance of understanding the molecular mechanisms underlying PD-L1 regulation [2]. Two groups coincidently identified CKLF-like MARVEL transmembrane domain containing protein 6 (CMTM6) as a critical factor controlling cell surface PD-L1 stability, albeit distinct

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