DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion

Abstract

RNA-binding proteins (RBPs) can recognize thousands of RNAs that help to maintain cell homeostasis, and RBP dysfunction is frequently observed in various cancers. However, whether specific RBPs are involved in tumor immune evasion by regulating programmed death ligand-1 (PD-L1) is unclear. Here, we perform targeted RBP CRISPR/Cas9 screening and identify density regulated re-initiation and release factor (DENR) as a PD-L1 regulator. DENR-depleted cancer cells exhibit reduced PD-L1 expression in vitro and in vivo. DENR depletion significantly suppresses tumor growth and enhances the tumor-killing activity of CD8+ T cells. Mechanistically, DENR antagonizes the translational repression of three consecutive upstream open reading frames (uORFs) upstream of Janus kinase 2 (Jak2); thus, DENR deficiency impairs JAK2 translation and the IFNγ-JAK-STAT signaling pathway, resulting in reduced PD-L1 expression in tumors. Overall, we discover an RBP DENR that could regulate PD-L1 expression for tumor immune evasion, and highlight the potential of DENR as a therapeutic target for immunotherapy.

Ruxolitinib and methylprednisolone for treatment of patients with relapsed/refractory multiple myeloma

“…5,20,21 JAKs have also been shown to increase expression of checkpoint proteins, including PD-L1. 27 BM from MM patients with PD shows increased expression of this protein and also the checkpoint protein B7H3. 13,15,16 Moreover, ruxolitinib blocks expression of these checkpoint proteins and increases anti-tumour T-cell activity in MM BM.…”

“…It has also been shown that JAK inhibitors have anti‐inflammatory effects that have led to their effective use to treat a variety of auto‐immune diseases, graft‐versus‐host disease and severe COVID‐19 infection 5,20,21 . JAKs have also been shown to increase expression of checkpoint proteins, including PD‐L1 27 . BM from MM patients with PD shows increased expression of this protein and also the checkpoint protein B7H3 13,15,16 .…”

Interleukin-3-Receptor-α in Triple-Negative Breast Cancer (TNBC): An Additional Novel Biomarker of TNBC Aggressiveness and a Therapeutic Target

“…PD-L1 is highly expressed in several cancer types [ 56 ] and much more in TNBCs compared with other breast cancer subtypes [ 57 ]. Genetic and epigenetic mechanisms, as well as inflammatory stimuli, control PD-L1 expression in cancers [ 58 , 59 ]. We demonstrated that IL-3Rα activation increases PD-L1 expression in primary tumours and in metastatic lung lesions, sustaining a role in the control of anti-tumour immune response.…”

Current insight into the regulation of PD-L1 in cancer

“…Tumor cells possess abundant PD-L1, which binds to the PD-1 receptor on the surface of tumor-infiltrating lymphocytes (TILs), subsequently sending immunosuppressive signals to TILs and preventing antigen-specific CD8 + T lymphocytes from eliminating tumor cells [ 13 – 16 ]. Moreover, PD-L1 enables the promotion of tumor therapy through non-T cell-mediated immunity.…”

“…PD-L1 upregulation occurs across a broad spectrum of cell types as a result of stimulation by proinflammatory cytokines and other factors, and PD-L1 is highly expressed in many cancer cells such as lung, ovarian, colon, and melanoma [11,12]. Tumor cells possess abundant PD-L1, which binds to the PD-1 receptor on the surface of tumor-infiltrating lymphocytes (TILs), subsequently sending immunosuppressive signals to TILs and preventing antigen-specific CD8 + T lymphocytes from eliminating tumor cells [13][14][15][16]. Moreover, PD-L1 enables the promotion of tumor therapy through non-T cell-mediated immunity.…”