Establishment of peripheral blood mononuclear cell-derived humanized lung cancer mouse models for studying efficacy of PD-L1/PD-1 targeted immunotherapy

Abstract

Animal models used to evaluate efficacies of immune checkpoint inhibitors are insufficient or inaccurate. We thus examined two xenograft models used for this purpose, with the aim of optimizing them. One method involves the use of peripheral blood mononuclear cells and cell line-derived xenografts (PBMCs-CDX model). For this model, we implanted human lung cancer cells into NOD-scid-IL2Rg−/− (NSI) mice, followed by injection of human PBMCs. The second method involves the use of hematopoietic stem and progenitor cells and CDX (HSPCs-CDX model). For this model, we first reconstituted the human immune system by transferring human CD34+ hematopoietic stem and progenitor cells (HSPCs-derived humanized model) and then transplanted human lung cancer cells. We found that the PBMCs-CDX model was more accurate in evaluating PD-L1/PD-1 targeted immunotherapies. In addition, it took only four weeks with the PBMCs-CDX model for efficacy evaluation, compared to 10-14 weeks with the HSPCs-CDX model. We then further established PBMCs-derived patient-derived xenografts (PDX) models, including an auto-PBMCs-PDX model using cancer and T cells from the same tumor, and applied them to assess the antitumor efficacies of anti-PD-L1 antibodies. We demonstrated that this PBMCs-derived PDX model was an invaluable tool to study the efficacies of PD-L1/PD-1 targeted cancer immunotherapies. Overall, we found our PBMCs-derived models to be excellent preclinical models for studying immune checkpoint inhibitors.

The Development of Next-generation PBMC Humanized Mice for Preclinical Investigation of Cancer Immunotherapeutic Agents

“…Humanized mice frequently develop exaggerated levels of Tcell exhaustion, which provide a larger target for immunotherapeutic modulation. In particular, the PBMC model offers greater up-regulation of markers of phenotypic exhaustion both in the tumor microenvironment and periphery (28,49). Increased presence and faster upregulation of exhaustion markers assist in the ability to screen for effective immunomodulatory agents.…”

The humanized mouse: Emerging translational potential

“…Of note, in a recently described NSG mouse strain lacking both murine MHC I and MHC II (major histocompatibility complex) expression, engraftment of human PBMCs did not immediately result in xenoGvH 19 . This notwithstanding, unless the tumor is acquired from a source identical to that of the T cells, they will also recognize it as a foreign tissue with an alloreactive response 41 …”

“…Likewise, T cells from PBMCs will not only immediately attack the murine host, but also any implanted xenograft not from an autologous source 15 . Of note, however, when PBMCs (or, in one study, ex vivo‐expanded and activated tumor‐infiltrating lymphocytes) from a tumor patient were injected into immunodeficient mice on which autologous PDX samples were subsequently implanted, the tumors responded to immune‐directed therapies in much the same manner as was observed in the patients, highlighting the possible utility of such a system in drug‐efficacy studies 41,84 …”

Mouse Tumor Models for Advanced Cancer Immunotherapy

“…For a reasonable time, it is necessary to successfully transplant a tumor into several animals, as well as reconstruct the patient's hematopoietic system [104]. In order to quickly restore the autologous human immune system in immunocompromised mice with the patient's tumors, PBMCs from adult donors can be used, since it is not necessary to wait for the formation of differentiated cells from HSCs up to 10-14 weeks [105,106]. PBMCs are also much easier to collect from patients and their engraftment time is reduced to four weeks [106].…”