Identification of WDFY3 Neoantigens as Prognostic Markers in Longterm Survivors of Extrahepatic Cholangiocarcinoma

Author(s): Yingyi Wang, Bao Jin, Na Zhou, Zhao Sun, Jiayi Li, Qiao Chen, Xiangan Wu, Yi Zhou, Yue Shi, Xin Lu, Xinting Sang, Yilei Mao, Shunda Du*, Wenze Wang*, Chunmei Bai*

Journal Name: Current Cancer Drug Targets

Volume 20 , Issue 11 , 2020


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Graphical Abstract:


Abstract:

Background: Neoantigens are newly formed antigens that have not been previously recognized by the immune system. They may arise from altered tumor proteins that form as a result of mutations. Although neoantigens have recently been linked to antitumor immunity in long-term survivors of cancers, such as melanoma and colorectal cancer, their prognostic and immune-modulatory role in many cancer types remains undefined.

Objective: The purpose of this study is to identify prognostic markers for long-term extrahepatic cholangiocarcinoma (EHCC) survival.

Methods: We investigated neoantigens in EHCC, a rare, aggressive cancer with a 5-year overall survival rate lower than 10%, using a combination of whole-exome sequencing (WES), RNA sequencing (RNA-seq), computational biophysics, and immunohistochemistry.

Results: Our analysis revealed a decreased neutrophil infiltration-related trend of high-quality neoantigen load with IC50 <500 nM (r=-0.445, P=0.043). Among 24 EHCC patients examined, we identified four long-term survivors with WDFY3 neoantigens and none with WDFY3 neoantigens in the short-term survivors. The WDFY3 neoantigens are associated with a lower infiltration of neutrophils (p=0.013), lower expression of CCL5 (p=0.025), CXCL9 (p=0.036) and TIGIT (p=0.016), and less favorable prognosis (p=0.030). In contrast, the prognosis was not significantly associated with tumor mutation burden, neoantigen load, or immune cell infiltration.

Conclusion: We suggest that the WDFY3 neoantigens may affect prognosis by regulating antitumor immunity and that the WDFY3 neoantigens may be harnessed as potential targets for immunotherapy of EHCC.

Keywords: Extrahepatic cholangiocarcinoma, WDFY3 neoantigens, prognosis, immune cell infiltration, immune signature genes, tumor mutation burden.

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VOLUME: 20
ISSUE: 11
Year: 2020
Page: [875 - 886]
Pages: 12
DOI: 10.2174/1568009620999200918121456
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