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bioRxiv · 10.1101/2020.05.24.112722

NK cells and CTLs are required to clear solid tumor in a novel model of patient-derived-xenograft

Le, D. T.·Burt, B.·Van Buren, G.·Abeynaike, S. A.·Zalfa, C.·Nikzad, R.·Kheradmand, F.·Paust, S.
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Abstract

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 (TIL) expanded in the recipient mice for several weeks. Tumors engrafted in about seventy to eighty percent of syngeneic-immune-system-PDX (SIS-PDX) mice, which harbored tumor-exhausted immune-effector and functional immune-regulatory cells persisting for at least six-months post-engraftment. Interleukin-15 (IL-15)-stimulation in addition to immune checkpoint inhibition (ICI), prevented resistance, resulting in complete or partial response to combined treatment. Further, the depletion of Cytotoxic T lymphocytes (CTLs) and/or Natural Killer (NK) cells from combined immunotherapy in SIS-PDX mice revealed that both cell types are required for the maximal response to tumor. Our novel SIS-PDX model provides a valuable resource for powerful mechanistic and therapeutic studies designed to eradicate solid tumors.

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Le, D. T., Burt, B., Van Buren, G., Abeynaike, S. A., Zalfa, C., Nikzad, R., Kheradmand, F., Paust, S.. 2020-05-26. NK cells and CTLs are required to clear solid tumor in a novel model of patient-derived-xenograft. https://doi.org/10.1101/2020.05.24.112722

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