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

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

doi:10.1172/jci.insight.140116

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.

Highlights

There is mounting experimental evidence documenting the importance of effector functions mediated by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells in the host immune response to cancer, both individually and collaboratively [1,2,3,4,5,6,7,8,9]
The frequency of NK cells was significantly decreased in Lung adenocarcinoma (LUAD), and fewer of these LUAD-resident NK cells expressed the activating receptor CD16 compared with donor-matched normal lung tissue (Figure 1, B and C)
These data suggest that programmed death receptor-1 (PD-1), PD-L1, and PD-L2 are expressed on lung tissue, and LUAD-resident NK cells and a significantly higher number of NK cells express PD-1, PD-L1, and/or PD-L2 in LUAD compared with nontumor lung tissue

Summary

Introduction

There is mounting experimental evidence documenting the importance of effector functions mediated by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells in the host immune response to cancer, both individually and collaboratively [1,2,3,4,5,6,7,8,9]. NK cells express a large number of activating and inhibitory receptors that mainly bind to self MHC-I [13, 14]. This is essential in the context of cancer recognition because MHC-I is often downregulated by malignant cells, circumventing CTL-mediated killing [15]. Stress ligands expressed by tumor cells can activate NK cells through activating receptors, such as NKG2D [14, 16,17,18] and CD16, the FcγRIII responsible for antibody-dependent cellular cytotoxicity [19]

Objectives

Methods

Results

Conclusion