Induction of cancer neoantigens facilitates development of clinically relevant models for the study of pancreatic cancer immunobiology

Neoantigen burden and CD8 T cell infiltrate are associated with clinical outcome in pancreatic ductal adenocarcinoma (PDAC). A shortcoming of many genetic models of PDAC is the lack of neoantigen burden and limited T cell infiltrate. The goal of the present study was to develop clinically relevant m...

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Published in:Cancer Immunology, Immunotherapy Immunotherapy, 2023-08, Vol.72 (8), p.2813-2827
Main Authors: Panni, Usman Y., Chen, Michael Y., Zhang, Felicia, Cullinan, Darren R., Li, Lijin, James, C. Alston, Zhang, Xiuli, Rogers, S., Alarcon, A., Baer, John M., Zhang, Daoxiang, Gao, Feng, Miller, Christopher A., Gong, Qingqing, Lim, Kian-Huat, DeNardo, David G., Goedegebuure, S. Peter, Gillanders, William E., Hawkins, William G.
Format: Article
Language:English
Subjects:
Adenocarcinoma
Antigen presentation
Antigens, Neoplasm
Cancer immunotherapy
Cancer Research
Carcinoma, Pancreatic Ductal - therapy
CD8 antigen
CD8-Positive T-Lymphocytes
Cell differentiation
Chemokines
Cloning
Humans
Immune checkpoint inhibitors
Immunogenicity
Immunology
Immunotherapy
Infiltration
Lymphocytes
Lymphocytes T
Medicine
Medicine & Public Health
Metastases
Neoantigens
Oncology
Oxaliplatin
Pancreatic cancer
Pancreatic Neoplasms - therapy
Tumors
Vaccines
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Summary:Neoantigen burden and CD8 T cell infiltrate are associated with clinical outcome in pancreatic ductal adenocarcinoma (PDAC). A shortcoming of many genetic models of PDAC is the lack of neoantigen burden and limited T cell infiltrate. The goal of the present study was to develop clinically relevant models of PDAC by inducing cancer neoantigens in KP2, a cell line derived from the KPC model of PDAC. KP2 was treated with oxaliplatin and olaparib (OXPARPi), and a resistant cell line was subsequently cloned to generate multiple genetically distinct cell lines (KP2-OXPARPi clones). Clones A and E are sensitive to immune checkpoint inhibition (ICI), exhibit relatively high T cell infiltration, and have significant upregulation of genes involved in antigen presentation, T cell differentiation, and chemokine signaling pathways. Clone B is resistant to ICI and is similar to the parental KP2 cell line in terms of relatively low T cell infiltration and no upregulation of genes involved in the pathways noted above. Tumor/normal exome sequencing and in silico neoantigen prediction confirms successful generation of cancer neoantigens in the KP2-OXPARPi clones and the relative lack of cancer neoantigens in the parental KP2 cell line. Neoantigen vaccine experiments demonstrate that a subset of candidate neoantigens are immunogenic and neoantigen synthetic long peptide vaccines can restrain Clone E tumor growth. Compared to existing models, the KP2-OXPARPi clones better capture the diverse immunobiology of human PDAC and may serve as models for future investigations in cancer immunotherapies and strategies targeting cancer neoantigens in PDAC.
ISSN:0340-7004
1432-0851
DOI:10.1007/s00262-023-03463-x