DNAJB1-PRKACA fusion neoantigens elicit rare endogenous T cell responses that potentiate cell therapy for fibrolamellar carcinoma
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 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
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.