ARIH1 signaling promotes anti-tumor immunity by targeting PD-L1 for proteasomal degradation

Abstract

Cancer expression of PD-L1 suppresses anti-tumor immunity. PD-L1 has emerged as a remarkable therapeutic target. However, the regulation of PD-L1 degradation is not understood. Here, we identify several compounds as inducers of PD-L1 degradation using a high-throughput drug screen. We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal degradation following GSK3α-mediated phosphorylation of Ser279/Ser283. We identify ARIH1 as the E3 ubiquitin ligase responsible for targeting PD-L1 to degradation. Overexpression of ARIH1 suppresses tumor growth and promotes cytotoxic T cell activation in wild-type, but not in immunocompromised mice, highlighting the role of ARIH1 in anti-tumor immunity. Moreover, combining EGFR inhibitor ES-072 with anti-CTLA4 immunotherapy results in an additive effect on both tumor growth and cytotoxic T cell activation. Our results delineate a mechanism of PD-L1 degradation and cancer escape from immunity via EGFR-GSK3α-ARIH1 signaling and suggest GSK3α and ARIH1 might be potential drug targets to boost anti-tumor immunity and enhance immunotherapies.

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“…Particularly, immune costimulatory molecules are one of the recent hotspots in immunology research, and PD-1 and its ligand PD-L1are important participants of tumor progression. PD-L1 is widely expressed in tumor cells, and it binds to PD-1 on the surface of T lymphocytes to transmit inhibitory signals to T cells, thereby inactivating T lymphocyte immune reactions [ 14 , 15 ]. Therefore, inhibition of the PD-1/PD-L1 pathway can enhance T cell function and facilitate tumor cell death, which is a new strategy for tumor therapy.…”

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“…PD-L1 is constitutively expressed on the surface of cancer cells, while the receptor of PD-L1, programmed death protein-1 (PD-1), is mostly expressed on the surface of T cells. Therefore, the interaction between them prevents cancer cells from immune surveillance of T cells ( 111 ). YAP/TAZ and PD-L1 have a bidirectional interaction in suppressing anti-tumor T cell responses.…”

Ubiquitination in T-Cell Activation and Checkpoint Inhibition: New Avenues for Targeted Cancer Immunotherapy

“…A study this year further implicated the GSK3α/ARIH1 as another kinase/E3 ligase pair inducing PD-L1 proteolysis. In this case, GSK3α-dependent phosphorylation of PD-L1 at S279/S283 is recognized by the E3 ligase ARIH1, followed by PD-L1 Lys48-ubiquitination and degradation [ 221 ] ( Figure 3 ). Whereas immunocompetent mice are able to reject cancer cell lines overexpressing the ARIH1 E3 ligase, immunocompromised mice are not, reinforcing the crucial role of ARIH1-ubiquitin-dependent pathways in anti-tumor immunity [ 221 ].…”

“…In this case, GSK3α-dependent phosphorylation of PD-L1 at S279/S283 is recognized by the E3 ligase ARIH1, followed by PD-L1 Lys48-ubiquitination and degradation [ 221 ] ( Figure 3 ). Whereas immunocompetent mice are able to reject cancer cell lines overexpressing the ARIH1 E3 ligase, immunocompromised mice are not, reinforcing the crucial role of ARIH1-ubiquitin-dependent pathways in anti-tumor immunity [ 221 ]. Recently, it was revealed that EGFR increases PD-L1 levels by additionally interfering with the membrane-bound MARCH8 E3 ligase, which also targets PD-L1 for degradation [ 222 ] ( Figure 3 ).…”