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Abstract
Introduction/Background Targeting programmed death 1(PD-1) has been approved for relapsed cervical cancer with unsatisfactory clinical efficacy. This study aims to analyze the impact of PI3K pathway activation on tumor immune microenvironment and evaluates the immune sensitization effect by PI3K inhibition in cervical cancer.
A. PD-L1 mRNA expression in cervical cancer tissues with wild-type PIK3CA (n=870) and mutant PIK3CA (n=145). B. PD-L1 expression in cervical cancer tissues with wild-type PIK3CA (n=133) and mutant PIK3CA (n=24), the representative image of PD-L1 expression with score 0–3+ was shown on the left, 1+ to 3+ was identified as PD-L1 positive. C. Schematic diagram of SiHa- and Caski-CDXs administration. D, E. Proliferation curve of tumor volumes measured during the tumor formation in the SiHa-CDXs (D) and Caski-CDX(E) treated with different drugs. F, G. Proliferation curve of tumor volumes after treatments with different drugs for 28 days in PDXs with wild-type PIK3CA(F) and PIK3CA-E545K mutation(G).
Methodology The effect of PIK3CA mutation on PD-L1 expression and CD8+ T cells differentiation was determined in cervical cancer tissues. Luciferase and ChIP-PCR assays were used to determine the transcriptional regulation of PD-L1 by PIK3CA-E545K. The effects of PI3K inhibitor treatment on immune tumor 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).
Results 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 a 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 inhibitors markedly activate immune microenvironment by regulating the PD-1/L1-related pathways and promotes CD8+ T cell differentiation, proliferation in Caski-CDXs with PIK3CA-E545K mutation. PI3Kα inhibitor significantly enhances the anti-tumor efficacy of PD-1 blockade in CDXs and PDXs.
Conclusion The efficacy of PI3K inhibitors combined with PD-1 antibodies is promising in cervical cancer and warrants additional clinical investigations.
Disclosures No.