Natural killer cells and cytotoxic T lymphocytes are required to clear solid tumor in a patient-derived xenograft
Duy Tri Le, … , John J. Tyner, Silke Paust
Duy Tri Le, … , John J. Tyner, Silke Paust
Published June 3, 2021
Citation Information: JCI Insight. ;6(13):e140116. https://doi.org/10.1172/jci.insight.140116.
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Resource and Technical Advance Immunology

Natural killer cells and cytotoxic T lymphocytes are required to clear solid tumor in a patient-derived xenograft

Abstract

Existing patient-derived xenograft (PDX) mouse models of solid tumors lack a fully tumor donor–matched, syngeneic, and functional immune system. We developed a model that overcomes these limitations 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 83% to 89% of TIL-PDX mice, and these were seen to harbor exhausted immuno-effector as well as functional immunoregulatory cells persisting for at least 6 months postengraftment. Combined treatment with interleukin-15 stimulation and immune checkpoint inhibition resulted in complete or partial tumor response in this model. Further, depletion of cytotoxic T lymphocytes and/or natural killer cells before combined immunotherapy revealed that both cell types were required for maximal tumor regression. Our TIL-PDX model provides a valuable resource for powerful mechanistic and therapeutic studies in solid tumors.

Authors

Duy Tri Le, Tridu R. Huynh, Bryan Burt, George Van Buren, Shawn A. Abeynaike, Cristina Zalfa, Rana Nikzad, Farrah Kheradmand, John J. Tyner, Silke Paust

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Figure 9

NK cells and CTLs are required for successful combination immunotherapy in the TIL-PDX-LUAD model.

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NK cells and CTLs are required for successful combination immunotherapy ...
(A) Fold change in tumor volume in TIL-PDX-LUAD mice treated with 100 μg/mouse blocking antibody against PD-1 and 5 μg/mouse IL-15 + 2.5 μg/mouse IL-15RαFc by intraperitoneal injection at day 0 and every 7 days after that. Control mice received saline. Experiments were started when tumors were about 50 ± 14 mm3 with no statistical size difference between experimental and control groups at day 0 and tumor volumes measured weekly. Three days prior to the start of PD-1 blockade + IL-15/IL-15RαFc therapy (day –3) as well as on days 0, 7, 14, 21, 28, 35, 42, and 49, CTLs and/or NK cells were depleted using 100 μg/mouse of antibody specific to human CD8a (OKT-8) to deplete CTLs, and/or antibody specific to NKp46 (9E2) to deplete NK cells, as indicated. Control mice received saline. (A) Mean fold change in tumor volume of each experimental or control group with SEM. (B) Mean fold change in tumor volume of TIL-PDX-LUAD mouse with SEM. Three independent experiments were performed using 3 genetically unrelated tumor donor cohorts and data pooled for analysis. Depending on cohort size, 2 to 3 TIL-PDX-LUAD mice each were analyzed from each cohort for n = 8 for untreated control group, n = 9 for IL-15 stimulation + PD-1 blockade, n = 6 for IL-15 stimulation + PD-1 blockade and NK cell depletion, n = 6 for IL-15 stimulation + PD-1 blockade and CTL depletion. Data are represented as mean ± SEM; multiple t tests, *,#P < 0.05; **,##P < 0.005; ***,###P < 0.0005; ****P < 0.00005.