Allison M Kirk, Jeremy Chase Crawford, Ching-Heng Chou, Cliff Guy, Kirti Pandey, Tanya Kozlik, Ravi K Shah, Shanzou Chung, Phuong Nguyen, Xiaoyu Zhang, Jin Wang, Matthew Bell, Robert C Mettelman, E Kaitlynn Allen, Mikhail V Pogorelyy, Hyunjin Kim, Anastasia A Minervina, Walid Awad, Resha Bajracharya, Toni White, Donald Long, Brittney Gordon, Michelle Morrison, Evan S Glazer, Andrew J Murphy, Yixing Jiang, Elizabeth A Fitzpatrick, Mark Yarchoan, Praveen Sethupathy, Nathan P Croft, Anthony W Purcell, Sara M Federico, Elizabeth Stewart, Stephen Gottschalk, Anthony E Zamora, Christopher DeRenzo, Scott E Strome, Paul G Thomas
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...
March 19, 2024: Cell reports medicine