No abstract

Targeting programmed death 1(PD‐1) has been approved for relapsed cervical cancer with unsatisfactory clinical efficacy. This study aims to analyse the impact of PI3K pathway activation on tumour immune microenvironment and evaluates the immune sensitization effect by PI3K inhibition in cervical cancer. The effect of PIK3CA mutation on PD‐L1 expression and CD8+ T cells differentiation was determined in cervical cancer tissues. Luciferase and ChIP‐qPCR/PCR assays were used to determine the transcriptional regulation of PD‐L1 by PIK3CA‐E545K. The effects of PI3K inhibitor treatment on immune environment in vitro and in vivo were evaluated by RNA sequencing (RNA‐seq) and flow cytometry. The efficacy of PI3K inhibitor and anti‐PD‐1 therapy was assessed in cell‐derived xenografts (CDX) and patients‐derived xenografts (PDX). PD‐L1 overexpression is more frequently observed in elder women with squamous cervical carcinoma. It predicts longer progress‐free survival and overall survival. PIK3CA mutation results in increased mRNA and protein levels of PD‐L1, the repression of CD8+ T cell differentiation in cervical cancer. Here, we report a case that continuous pembrolizumab monotherapy treatment induced complete remission of a recurrent cervical cancer patient with systemic metastasis and PIK3CA‐E545K mutation, implying that PIK3CA mutation is potentially a biomarker for pembrolizumab treatment in cervical cancer. Specifically, this mutation promotes the expression of PD‐L1 by upregulating the transcription factor IRF1. PI3Kα‐specific inhibitor markedly activates immune microenvironment by regulating the PD‐1/L1‐related pathways and promoting CD8+ T cell differentiation and proliferation in Caski‐CDXs with PIK3CA‐E545K mutation. PI3Kα inhibitor significantly enhances the anti‐tumour efficacy of PD‐1 blockade in CDXs and PDXs. PIK3CA mutations may predict the response of cervical cancer to PD‐1 blockade. The efficacy of PI3Kα inhibitors combined with PD‐1 antibodies is promising in cervical cancer and warrants additional clinical and mechanistic investigations.

Peritoneal implantation and lymph node metastasis have different driving mechanisms in ovarian cancer. Elucidating the underlying mechanism of lymph node metastasis is important for treatment outcomes. A new cell line, FDOVL, was established from a metastatic lymph node of a patient with primary platinum-resistant ovarian cancer and was then characterized. The effect of NOTCH1-p.C702fs mutation and NOTCH1 inhibitor on migration was evaluated in vitro and in vivo. Ten paired primary sites and metastatic lymph nodes were analyzed by RNA sequencing. The FDOVL cell line with serious karyotype abnormalities could be stably passaged and could be used to generated xenografts. NOTCH1-p.C702fs mutation was found exclusively in the FDOVL cell line and the metastatic lymph node. The mutation promoted migration and invasion in cell and animal models, and these effects were markedly repressed by the NOTCH inhibitor LY3039478. RNA sequencing confirmed CSF3 as the downstream effector of NOTCH1 mutation. Furthermore, the mutation was significantly more common in metastatic lymph nodes than in other peritoneal metastases in 10 paired samples (60% vs. 20%). The study revealed that NOTCH1 mutation is probably a driver of lymph node metastasis in ovarian cancer, which offers new ideas for the treatment of ovarian cancer lymph node metastasis with NOTCH inhibitors.