PD-L1 expression is regulated by ATP-binding of the ERBB3 pseudokinase domain.

How PD-L1 expression is regulated in cancer is poorly understood. Here, we report that the ATP-binding activity of ERBB3 pseudokinase regulates PD-L1 gene expression in colorectal cancers (CRCs). ERBB3 is one of the four members of the EGF receptor family, all with protein tyrosine kinase domains. ERBB3 is a pseudokinase with a high binding affinity to ATP. We showed that ERBB3 ATP-binding inactivation mutant reduces tumorigenicity in genetically engineered mouse models and impairs xenograft tumor growth of CRC cell lines. The ERBB3 ATP-binding mutant cells dramatically reduce IFN-γ-induced PD-L1 expression. Mechanistically, ERBB3 regulates IFN-γ-induced PD-L1 expression through the IRS1-PI3K-PDK1-RSK-CREB signaling axis. CREB is the transcription factor that regulates PD-L1 gene expression in CRC cells. Knockin of a tumor-derived ERBB3 mutation located in the kinase domain sensitizes mouse colon cancers to anti-PD1 antibody therapy, suggesting that ERBB3 mutations could be predictive biomarkers for tumors amenable to immune checkpoint therapy.

癌症中PD - L1的表达是如何调控的，人们知之甚少。在此，我们报道ERBB3假激酶的ATP结合活性调控结直肠癌（CRCs）中PD - L1基因的表达。ERBB3是表皮生长因子受体家族四个成员之一，都具有蛋白酪氨酸激酶结构域。ERBB3是一种对ATP具有高结合亲和力的假激酶。我们发现ERBB3的ATP结合失活突变体在基因工程小鼠模型中降低了致瘤性，并抑制了结直肠癌细胞系的异种移植肿瘤生长。ERBB3的ATP结合突变体细胞显著降低了干扰素 - γ诱导的PD - L1表达。从机制上讲，ERBB3通过IRS1 - PI3K - PDK1 - RSK - CREB信号轴调控干扰素 - γ诱导的PD - L1表达。CREB是调控结直肠癌细胞中PD - L1基因表达的转录因子。在激酶结构域敲入一种源自肿瘤的ERBB3突变，可使小鼠结肠癌对抗PD1抗体治疗敏感，这表明ERBB3突变可能是适合免疫检查点治疗的肿瘤的预测性生物标志物。