TY - JOUR
T1 - Identification of tumor antigens in the HLA peptidome of patient-derived xenograft tumors in mouse
AU - Rijensky, Nataly Mancette
AU - Blondheim Shraga, Netta R.
AU - Barnea, Eilon
AU - Peled, Nir
AU - Rosenbaum, Eli
AU - Popovtzer, Aron
AU - Stemmer, Solomon M.
AU - Livoff, Alejandro
AU - Shlapobersky, Mark
AU - Moskovits, Neta
AU - Perry, Dafna
AU - Rubin, Eitan
AU - Haviv, Itzhak
AU - Admon, Arie
N1 - Funding Information:
This work was supported by the Israel Ministry of Science grant 3-11176 to Itzhak Haviv, Arie Admon and Eitan Rubin, and by the Israel Science Foundation, grants 1435/16 to Arie Admon. The mass spectrometry was performed in the Smoler Proteomics Center of the Technion and the technical help of Ms. Ilana Navon is much appreciated. The HLA typing was performed by the Tissue Typing and Immunogenetics Laboratory in Hadassah Medical Organization and the professional help of Ms. Keren Miller is much appreciated. Dr. Dganit Melamed Kadosh and Ms. Micòl Melchers's help in data analyses and writing is also much appreciated.
Funding Information:
This work was supported by the Israel Ministry of Science grant 3-11176 to Itzhak Haviv, Arie
Funding Information:
Admon and Eitan Rubin, and by the Israel Science Foundation, grants 1435/16 to Arie Admon.
Publisher Copyright:
© 2020 American Society for Biochemistry and Molecular Biology Inc.. All rights reserved.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - Personalized cancer immunotherapy targeting patient-specific cancer/testis antigens (CTA) and neoantigens may benefit from large-scale tumor human leukocyte antigen (HLA) peptidome (immunopeptidome) analysis, which aims to accurately identify antigens presented by tumor cells. While significant efforts have been invested in analyzing the HLA peptidomes of fresh tumors, it is often impossible to obtain sufficient volumes of tumor tissues for comprehensive HLA peptidome characterization. This work attempted to overcome some of these obstacles by using patient-derived xenograft tumors (PDX) in mice as the tissue sources for HLA peptidome analysis. PDX tumors provide a proxy for the expansion of the patient tumor by re-grafting them through several passages to immune-compromised mice. The HLA peptidomes of human biopsies were compared to those derived from PDX tumors. Larger HLA peptidomes were obtained from the significantly larger PDX tumors as compared to the patient biopsies. The HLA peptidomes of different PDX tumors derived from the same source tumor biopsy were very reproducible, even following subsequent passages to new naïve mice. A large number of CTA-derived HLA peptides were discovered, as well as several potential neoantigens/variant sequences. Taken together, the use of PDX tumors for HLA peptidome analysis serves as a highly expandable and stable source of reproducible and authentic peptidomes, opening up new opportunities for defining large HLA peptidomes when only small tumor biopsies are available. This approach provides a large source for tumor antigens identification, potentially useful for personalized immunotherapy.
AB - Personalized cancer immunotherapy targeting patient-specific cancer/testis antigens (CTA) and neoantigens may benefit from large-scale tumor human leukocyte antigen (HLA) peptidome (immunopeptidome) analysis, which aims to accurately identify antigens presented by tumor cells. While significant efforts have been invested in analyzing the HLA peptidomes of fresh tumors, it is often impossible to obtain sufficient volumes of tumor tissues for comprehensive HLA peptidome characterization. This work attempted to overcome some of these obstacles by using patient-derived xenograft tumors (PDX) in mice as the tissue sources for HLA peptidome analysis. PDX tumors provide a proxy for the expansion of the patient tumor by re-grafting them through several passages to immune-compromised mice. The HLA peptidomes of human biopsies were compared to those derived from PDX tumors. Larger HLA peptidomes were obtained from the significantly larger PDX tumors as compared to the patient biopsies. The HLA peptidomes of different PDX tumors derived from the same source tumor biopsy were very reproducible, even following subsequent passages to new naïve mice. A large number of CTA-derived HLA peptides were discovered, as well as several potential neoantigens/variant sequences. Taken together, the use of PDX tumors for HLA peptidome analysis serves as a highly expandable and stable source of reproducible and authentic peptidomes, opening up new opportunities for defining large HLA peptidomes when only small tumor biopsies are available. This approach provides a large source for tumor antigens identification, potentially useful for personalized immunotherapy.
UR - http://www.scopus.com/inward/record.url?scp=85089128767&partnerID=8YFLogxK
U2 - 10.1074/mcp.RA119.001876
DO - 10.1074/mcp.RA119.001876
M3 - Article
C2 - 32451349
AN - SCOPUS:85089128767
VL - 19
SP - 1360
EP - 1374
JO - Molecular and Cellular Proteomics
JF - Molecular and Cellular Proteomics
SN - 1535-9476
IS - 8
ER -