Establishment of Humanized Mice from Peripheral Blood Mononuclear Cells or Cord Blood CD34+ Hematopoietic Stem Cells for Immune-Oncology Studies Evaluating New Therapeutic Agents

Authors:
Bhavna Verma , Amy Wesa 
In:
Source: Curr Protoc Immunol
Publication Date: (2020)
Issue: 89: 1
Research Area:
Cancer Research/Cell Biology
Immunotherapy / Hematology
Stem Cells
Cells used in publication:
CD34+ cell, human
Species: human
Tissue Origin: blood
PBMC, human
Species: human
Tissue Origin: blood
Experiment

The Lonza cells were thawed and washed with PBS and directly used. Here are the details:

Thaw cryopreserved cord blood huCD34+HSCs (1×106 CB-CD34+cells per vial for 8 to 10 mice) in a 37°Cwater bath until a sliver of ice remains. Then, transfer cells

to a 15-ml polypropylene tube in a class II BSC and wash twice in 10 ml of 1× PBS at room temperature, with centrifugation for 5 min at 300×g. Resuspend cells in 0.5

to 1 ml RPMI-1640 medium and count viable cells either manually, using a hematocytometer, trypan blue, and a light microscope, or with an automated cell counter. 3. Adjust concentration of huCD34+ HSCs by resuspension to 6 × 105 cells/ml in RPMI-1460 and store cells briefly on ice prior to injection. Using a 1-cc tuberculin syringe with a 25-G × ?-in. needle, inject 0.2 ml (1.2 × 105 HSCs) into lateral tail vein of each irradiated mouse by intravenous (IV) injection.

Abstract

The clinical success of immune checkpoint modulators and the development of next-generation immune-oncology (IO) agents underscore the need for robust preclinical models to evaluate novel IO therapeutics. Human immune system (HIS) mouse models enable in vivo studies in the context of the HIS via a human tumor. The immunodeficient mouse strains NOG (Prkdcscid Il2rgtm1Sug ) and triple-transgenic NOG-EXL [Prkdcscid Il2rgtm1Sug Tg (SV40/HTLV-IL3, CSF2)], which expresses human IL-3 and GM-CSF, allow for human CD34+ hematopoietic stem cell (huCD34+ HSC) engraftment and multilineage immune cell development by 12 to 16 weeks post-transplant and facilitate studies of immunomodulatory agents. A more rapid model of human immune engraftment utilizes peripheral blood mononuclear cells (PBMCs) transplanted into immunodeficient murine hosts, permitting T-cell engraftment within 2 to 3 weeks without outgrowth of other human immune cells. The PBMC-HIS model can be limited due to onset of xenogeneic graft-versus-host disease (xGVHD) within 3 to 5 weeks post-implantation. Host deficiency in MHC class I, as occurs in beta-2 microglobulin knockout in either NOG or NSG mice, results in resistance to xGVHD, which permits a longer therapeutic window. In this article, detailed processes for generating humanized mice by transplantation of HSCs from cord blood-derived huCD34+ HSCs or PBMCs into immunodeficient mouse strains to respectively generate HSC-HIS and PBMC-HIS mouse models are provided. In addition, the co-engraftment and growth kinetics of patient-derived and cell line-derived xenograft tumors in humanized mice and recovery of tumor-infiltrating lymphocytes from growing tumors to evaluate immune cell subsets by flow cytometry are described. © 2020 The Authors. Basic Protocol 1: Establishment of patient-derived xenograft tumors in CD34+ hematopoietic stem cell-humanized mice Basic Protocol 2: Establishment of patient-derived xenograft tumors in peripheral blood mononuclear cell-humanized mice Support Protocol 1: Flow cytometry assessment of humanization in mice Support Protocol 2: Flow cytometry assessment of tumor-infiltrating lymphocytes in tumor-bearing humanized mouse models.