Identification of CD318, TSPAN8 and CD66c as target candidates for CAR T cell based immunotherapy of pancreatic adenocarcinoma.
Adenocarcinoma
/ genetics
Animals
Antigens, CD
/ metabolism
Antigens, Neoplasm
/ genetics
Carcinoma, Pancreatic Ductal
/ metabolism
Cell Adhesion Molecules
/ genetics
Cell Line, Tumor
Cytokines
/ metabolism
GPI-Linked Proteins
/ metabolism
Gene Expression Regulation, Neoplastic
Heterografts
Humans
Immunologic Factors
Immunotherapy
/ methods
Lymphocyte Activation
Mice
Pancreatic Neoplasms
/ genetics
T-Lymphocytes
/ immunology
Tetraspanins
/ genetics
Pancreatic Neoplasms
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
05 03 2021
05 03 2021
Historique:
received:
21
04
2020
accepted:
09
02
2021
entrez:
6
3
2021
pubmed:
7
3
2021
medline:
20
3
2021
Statut:
epublish
Résumé
A major roadblock prohibiting effective cellular immunotherapy of pancreatic ductal adenocarcinoma (PDAC) is the lack of suitable tumor-specific antigens. To address this challenge, here we combine flow cytometry screenings, bioinformatic expression analyses and a cyclic immunofluorescence platform. We identify CLA, CD66c, CD318 and TSPAN8 as target candidates among 371 antigens and generate 32 CARs specific for these molecules. CAR T cell activity is evaluated in vitro based on target cell lysis, T cell activation and cytokine release. Promising constructs are evaluated in vivo. CAR T cells specific for CD66c, CD318 and TSPAN8 demonstrate efficacies ranging from stabilized disease to complete tumor eradication with CD318 followed by TSPAN8 being the most promising candidates for clinical translation based on functionality and predicted safety profiles. This study reveals potential target candidates for CAR T cell based immunotherapy of PDAC together with a functional set of CAR constructs specific for these molecules.
Identifiants
pubmed: 33674603
doi: 10.1038/s41467-021-21774-4
pii: 10.1038/s41467-021-21774-4
pmc: PMC7935963
doi:
Substances chimiques
Antigens, CD
0
Antigens, Neoplasm
0
CDCP1 protein, human
0
CEACAM6 protein, human
0
Cell Adhesion Molecules
0
Cytokines
0
GPI-Linked Proteins
0
Immunologic Factors
0
TSPAN8 protein, human
0
Tetraspanins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
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