Modulation of immune checkpoints has emerged as a highly promising therapeutic strategy in cancer treatment, demonstrating remarkable efficacy in numerous clinical trials. However, the underlined molecular mechanism(s) for moderate response rate (15-40%) or resistance to PD-1/PD-L1 blockade remains not completely understood. So far, differential PD-L1 levels have been linked with resistance to the immune checkpoint blockade. Therefore, deciphering the mechanistic pathways that control PD-L1 expression and stability may improve the efficacy of the immune-checkpoint inhibitors in cancer patients. WWP1 is an oncogenic HECT-type ubiquitin E3 ligase, which is found frequently amplified and mutated in multiple cancers, as well as in the germ line of patients with cancer susceptibility. Here we identify WWP1 as a previously uncharacterized regulator of PD-L1. We show that WWP1 triggers non-degradative K63-linked poly-ubiquitination of PD-L1, counteracting its K48-linked poly-ubiquitination and concomitant proteasomal degradation. This mechanism stabilizes PD-L1 expression and suppresses cytotoxic T-cell activity. We further demonstrate that the genetic ablation or pharmacological inhibition of WWP1 using Indole-3-carbinol, a natural compound found in Brassicaceae, profoundly reduces PD-L1 protein levels and enhanced CD8+ T-cell recruitment, infiltration, and tumor suppression in vivo. Thus, our study uncovers a novel and druggable regulatory node of PD-L1 protein stability by an oncogenic E3 ligase and reveals a potential combined therapeutic strategy to utilize the WWP1 inhibitor, Indole-3-carbinol, and anti-CTLA4 blockade for enhancing anti-tumor efficacy.
ONCOGENIC WWP1 E3 LIGASE STABILIZES PD-L1 THROUGH K63-LINKED POLYUBIQUITINATION: IMPLICATIONS FOR CANCER IMMUNE SURVEILLANCE AND IMMUNOTHERAPY
Centomo, Maria Laura
2023-01-01
Abstract
Modulation of immune checkpoints has emerged as a highly promising therapeutic strategy in cancer treatment, demonstrating remarkable efficacy in numerous clinical trials. However, the underlined molecular mechanism(s) for moderate response rate (15-40%) or resistance to PD-1/PD-L1 blockade remains not completely understood. So far, differential PD-L1 levels have been linked with resistance to the immune checkpoint blockade. Therefore, deciphering the mechanistic pathways that control PD-L1 expression and stability may improve the efficacy of the immune-checkpoint inhibitors in cancer patients. WWP1 is an oncogenic HECT-type ubiquitin E3 ligase, which is found frequently amplified and mutated in multiple cancers, as well as in the germ line of patients with cancer susceptibility. Here we identify WWP1 as a previously uncharacterized regulator of PD-L1. We show that WWP1 triggers non-degradative K63-linked poly-ubiquitination of PD-L1, counteracting its K48-linked poly-ubiquitination and concomitant proteasomal degradation. This mechanism stabilizes PD-L1 expression and suppresses cytotoxic T-cell activity. We further demonstrate that the genetic ablation or pharmacological inhibition of WWP1 using Indole-3-carbinol, a natural compound found in Brassicaceae, profoundly reduces PD-L1 protein levels and enhanced CD8+ T-cell recruitment, infiltration, and tumor suppression in vivo. Thus, our study uncovers a novel and druggable regulatory node of PD-L1 protein stability by an oncogenic E3 ligase and reveals a potential combined therapeutic strategy to utilize the WWP1 inhibitor, Indole-3-carbinol, and anti-CTLA4 blockade for enhancing anti-tumor efficacy.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
