DNAJB1-PRKACA fusion neoantigens elicit rare endogenous T cell responses that potentiate cell therapy for fibrolamellar carcinoma. Cell Rep Med 2024 Mar 19;5(3):101469
Date
03/21/2024Pubmed ID
38508137Pubmed Central ID
PMC10983114DOI
10.1016/j.xcrm.2024.101469Scopus ID
2-s2.0-85188438525 (requires institutional sign-in at Scopus site)Abstract
Fibrolamellar carcinoma (FLC) is a liver tumor with a high mortality burden and few treatment options. A promising therapeutic vulnerability in FLC is its driver mutation, a conserved DNAJB1-PRKACA gene fusion that could be an ideal target neoantigen for immunotherapy. In this study, we aim to define endogenous CD8 T cell responses to this fusion in FLC patients and evaluate fusion-specific T cell receptors (TCRs) for use in cellular immunotherapies. We observe that fusion-specific CD8 T cells are rare and that FLC patient TCR repertoires lack large clusters of related TCR sequences characteristic of potent antigen-specific responses, potentially explaining why endogenous immune responses are insufficient to clear FLC tumors. Nevertheless, we define two functional fusion-specific TCRs, one of which has strong anti-tumor activity in vivo. Together, our results provide insights into the fragmented nature of neoantigen-specific repertoires in humans and indicate routes for clinical development of successful immunotherapies for FLC.
Author List
Kirk AM, Crawford JC, Chou CH, Guy C, Pandey K, Kozlik T, Shah RK, Chung S, Nguyen P, Zhang X, Wang J, Bell M, Mettelman RC, Allen EK, Pogorelyy MV, Kim H, Minervina AA, Awad W, Bajracharya R, White T, Long D Jr, Gordon B, Morrison M, Glazer ES, Murphy AJ, Jiang Y, Fitzpatrick EA, Yarchoan M, Sethupathy P, Croft NP, Purcell AW, Federico SM, Stewart E, Gottschalk S, Zamora AE, DeRenzo C, Strome SE, Thomas PGAuthor
Anthony E. Zamora PhD Assistant Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Carcinoma, HepatocellularCell- and Tissue-Based Therapy
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
HSP40 Heat-Shock Proteins
Humans
Receptors, Antigen, T-Cell
T-Lymphocytes
