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