NK cells and CTLs are required to clear solid tumor in a novel model of 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 such a model by engrafting lymphopenic recipient mice with a fresh undisrupted piece of solid tumor, whereby tumorinfiltrating 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.

Natural Killer Cell Interactions With Myeloid Derived Suppressor Cells in the Tumor Microenvironment and Implications for Cancer Immunotherapy

“…The addition of IL-15 to PD-1 blockade completely abrogated tumor escape from ICI, resulting in a powerful additive therapeutic effect capable of tumor eradication. These findings support a key role for adjuvant IL-15 treatment to induce an immune cell-mediated tumor attack, which can prevent tumor escape from checkpoint blockade therapy, as shown using our novel LUAD-SIS-PDX model (418).…”

“…One of our preclinical studies found that the combination of PD-1 blockade and IL-15 signaling resulted in eradication of transplanted lung adenocarcinoma (LUAD) cells in about one-half of treated LUAD-SIS-PDX mice, while the other half presented with a partial response. Notably, IL-15 alone, without PD-1 blockade, significantly reduced tumor burden in all treated LUAD-SIS-PDX animals ( 418 ). PD-1 blockade alone transiently prevented tumor growth, but tumors grew at a similar rate to untreated control tumors after 2 weeks.…”

“…Combination therapies of PD-1 blockade and IL-15 stimulation and also IL-15 and IL-15RaFc have been reported as safe in mouse models ( 418 ) and patients with NSCLC ( 419 ). IL-15 stimulation increases the expression of the activating receptors CD16 and NKG2D on NK cells and increases the activation, proliferation, cytotoxic activity, and survival of NK cells and CTLs ( 420 ).…”

Interdependence of sequential cytotoxic T lymphocyte and natural killer cell cytotoxicity against melanoma cells

“…Expression of HLA class I was increased in melanoma cells when insufficient numbers of NK cells were present to eradicate all melanoma cells (Balsamo et al, 2012;Huergo-Zapico et al, 2018). Kohlhapp et al (2015) and Xu et al (2004) the eradication of melanoma, and Le et al (2020) found that both CTL and NK cells are important for control of solid tumours in a novel patient-derived xenograft model. Neubert et al (2016) developed a well-controlled co-culture assay for human melanoma and CTL to analyse future T cell-based immunotherapies.…”

Interdependence of CTL and NK cell cytotoxicity against melanoma cells

“…HLA class I expression was increased in melanoma cells in case insufficient NK cell numbers were present to eradicate all melanoma cells (Balsamo et al , 2012; Huergo-Zapico et al , 2018). Kohlhapp et al and Xu et al analysed the roles of murine CTL and NK cells with the result that both cytotoxic cell types are involved in the eradication of melanoma (Xu et al , 2004; Kohlhapp et al , 2015), and in addition Le et al found that both CTL and NK cells are important to control solid tumours in a novel patient-derived xenograft model (Le et al , 2020). Neubert et al developed a well-controlled co-culture assay for human melanoma and CTL to analyse future T-cell based immunotherapies (Neubert et al , 2016).…”