Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression

TLDR

PD‑1 ligands PD‑L1 and PD‑L2 are induced by interferon in tumors, enabling immune evasion and making them central to PD‑1 blockade immunotherapy. The study aimed to identify the specific molecules that mediate interferon‑induced regulation of PD‑L1 and PD‑L2 in melanoma cells. They investigated the interferon‑gamma signaling cascade, focusing on the JAK1/JAK2‑STAT1/STAT2/STAT3‑IRF1 axis and its binding to the PD‑L1 and PD‑L2 promoters. The results showed that PD‑L1 is mainly regulated by the interferon‑gamma‑JAK1/JAK2‑STAT1/STAT2/STAT3‑IRF1 pathway, while PD‑L2 responds to both interferon‑beta and gamma via IRF1 and STAT3, and melanoma biopsies confirmed enrichment of these transcriptional signatures in responders to anti‑PD‑1 therapy.

Abstract

PD-L1 and PD-L2 are ligands for the PD-1 immune inhibiting checkpoint that can be induced in tumors by interferon exposure, leading to immune evasion. This process is important for immunotherapy based on PD-1 blockade. We examined the specific molecules involved in interferon-induced signaling that regulates PD-L1 and PD-L2 expression in melanoma cells. These studies revealed that the interferon-gamma-JAK1/JAK2-STAT1/STAT2/STAT3-IRF1 axis primarily regulates PD-L1 expression, with IRF1 binding to its promoter. PD-L2 responded equally to interferon beta and gamma and is regulated through both IRF1 and STAT3, which bind to the PD-L2 promoter. Analysis of biopsy specimens from patients with melanoma confirmed interferon signature enrichment and upregulation of gene targets for STAT1/STAT2/STAT3 and IRF1 in anti-PD-1-responding tumors. Therefore, these studies map the signaling pathway of interferon-gamma-inducible PD-1 ligand expression.