Existing patient-derived-xenograft (PDX) mouse models of solid tumors lack a fully tumor-donor matched, syngeneic, and functional immune system. We developed such a model by engrafting lymphopenic recipient mice with a fresh, undisrupted piece of solid tumor, whereby tumor-infiltrating lymphocytes (TILs) persisted in the recipient mice for several weeks. Successful tumor engraftment was achieved in eighty-three to eighty-nine percent of tumor-infiltrating-lymphocytes-PDX (TIL-PDX) mice, and these were seen to harbor exhausted immuno-effector as well as functional immuno-regulatory cells persisting for at least six months post-engraftment. Combined treatment with interleukin-15 (IL-15) stimulation and immune checkpoint inhibition (ICI) resulted in complete or partial tumor response in this model. Further, depletion of Cytotoxic T-lymphocytes (CTLs) and/or Natural Killer (NK) cells before combined immunotherapy revealed that both cell types were required for maximal tumor regression. Our novel TIL-PDX model provides a valuable resource for powerful mechanistic and therapeutic studies in solid tumors.
Duy T. Le, Tridu R. Huynh, Bryan M. Burt, George Van Buren, Shawn A. Abeynaike, Cristina Zalfa, Rana Nikzad, Farrah Kheradmand, John J. Tyner, Silke Paust