Natural killer cells and cytotoxic T lymphocytes are required to clear solid tumor in a patient-derived xenograft
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
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
View: Text | PDF
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

×

Figure 5

Reconstituted TILs in TIL-PDX-PDAC mice retain human donor PDAC immune phenotypes.

Options: View larger image (or click on image) Download as PowerPoint
Reconstituted TILs in TIL-PDX-PDAC mice retain human donor PDAC immune p...
Flow cytometry of human immune cells from PBMCs, spleen, and transplanted PDAC of TIL-PDX-PDAC mice analyzed 4 to 6 months posttransplant. (A) Frequency of total human leukocytes (human CD45+); (B) frequency of human NK cells (hCD45+CD3–CD56+); (C) frequency of CD16- and/or NKG2D-expressing human NK cells; (D) frequency of PD-1–, PD-L1–, and/or PD-L2–expressing human NK cells; (E) frequency of CD3+ T cells; (F) frequency of PD-1–, PD-L1–, and/or PD-L2–expressing human CD3+ T cells; (G) frequency of CD8+ T cells (hCD45+CD3+CD8+) and CD4+ T cells (hCD45+CD3+CD4+); and (H) frequency of Tregs (hCD45+CD3+CD4+Foxp3+), as percentage of the CD4+ T cell subset in indicated tissues of TIL-PDX-PDAC mice. PBMC: Five genetically unrelated donor-cohorts were analyzed. Depending on cohort size, 3 to 6 TIL-PDX-PDAC mice of each cohort were analyzed, resulting in 15 to 30 data points total per cell type/marker and time point. Spleen and transplanted PDAC: Four genetically unrelated donor cohorts were analyzed. Depending on cohort size, 3 to 5 TIL-PDX-PDAC mice of each cohort were analyzed at each time point, resulting in 12–20 data points total per cell type/marker and time point. Data are represented as mean ± SEM; 1-way ANOVA with post hoc Tukey’s test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.