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Using PBMCs in Humanized Mouse Models for Preclinical Oncology Research

Mar 31, 2022 11:47:17 AM / by Champions Oncology

Lymphocyte. Closeup view of T-cell or B-cell

Humanized Immune System (HIS) have been used widely across biomedical research because they express a full complement of human immune cells and can tolerate tissue or tumor grafts. These attributes make the well-suited for preclinical studies of potential cancer therapies, including immune checkpoint inhibitors and adoptive cell therapies.

 

Several different immunodeficient mouse lines are used for HIS models, and each model has characteristics that are suited to different applications[1]. NSG mice have a severe combined immunodeficiency (SCID) mutation and a deletion of Il2rg, NRG mice are Rag and Il2rg knockouts, and NOG carry the SCID mutation and have a deletion in the Il2rg cytoplasmic domain. NSG is one of the most used HIS models and can be engrafted relatively easily with human PBMCs, and more recent models have been modified to be deficient in MHC class I and MHC class II for improved graft tolerance. Not only can HIS mice accept PBMCs and develop a full complement of human immune cell subsets, but they can also be engrafted with tumor cell lines or patient-derived xenografts, and this has been especially useful for evaluating the efficacy of immune checkpoint inhibitors like anti-programmed death-1 (PD-1)[2]. Similarly, transgenic T cells that express tumor-specific T cell receptors can be tested for their ability to target tumors[3].

0407_InsideBlog2Regulatory T cells (Tregs) are a T cell subset of great interest in preclinical oncology research because they have immunosuppressive properties that limit the effects of anti-tumor responses and promote immune evasion of tumor cells[4]. Tregs are especially problematic in the tumor microenvironment (TME) of solid tumors like breast cancer, non-small cell lung cancer and colorectal cancer[5],[6]. Tregs express immune checkpoint molecules like PD-1 and cytotoxic T-lymphocyte associated protein 4 (CTLA4), which can be engaged by tumor cells and further enhance immune suppression[7]. Immune checkpoint molecules are also expressed on conventional T cells, and engagement with their ligands on tumor cells results in T cell apoptosis. Critical studies in HIS mice have demonstrated that immune checkpoint inhibitors, like anti-PD-1 or anti-CTLA4, can deplete Tregs and reduce toxicity associated with adjuvant therapies like IL-2[8].

 

HIS models continue to be refined for specific cancer immunotherapy applications, which may include targeting of specific cell subsets like NK cells or dendritic cells. Advances in gene-targeting technology and applications with patient-derived PBMCs will allow HIS mice to serve as better models for personalized medicine.


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[1] Morillon YM 2nd, Sabzevari A, Schlom J, Greiner JW. The Development of Next-generation PBMC Humanized Mice for Preclinical Investigation of Cancer Immunotherapeutic Agents. Anticancer Res. 2020 Oct;40(10):5329-5341.

[2] Wang M, Yao LC, Cheng M, Cai D, Martinek J, Pan CX, Shi W, Ma AH, De Vere White RW, Airhart S, Liu ET, Banchereau J, Brehm MA, Greiner DL, Shultz LD, Palucka K, Keck JG. Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy. FASEB J. 2018 Mar;32(3):1537-1549.

[3] Hu Z, Xia J, Fan W, Wargo J, Yang YG. Human melanoma immunotherapy using tumor antigen-specific T cells generated in humanized mice. Oncotarget. 2016 Feb 9;7(6):6448-59.

[4] De Simone M, Arrigoni A, Rossetti G, Gruarin P, Ranzani V, Politano C, Bonnal RJP, Provasi E, Sarnicola ML, Panzeri I, Moro M, Crosti M, Mazzara S, Vaira V, Bosari S, Palleschi A, Santambrogio L, Bovo G, Zucchini N, Totis M, Gianotti L, Cesana G, Perego RA, Maroni N, Pisani Ceretti A, Opocher E, De Francesco R, Geginat J, Stunnenberg HG, Abrignani S, Pagani M. Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness of Tumor-Infiltrating T Regulatory Cells. Immunity. 2016 Nov 15;45(5):1135-1147.

[5] Gobert M, Treilleux I, Bendriss-Vermare N, Bachelot T, Goddard-Leon S, Arfi V, Biota C, Doffin AC, Durand I, Olive D, Perez S, Pasqual N, Faure C, Ray-Coquard I, Puisieux A, Caux C, Blay JY, Ménétrier-Caux C. Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res. 2009 Mar 1;69(5):2000-9.

[6] Fu J, Xu D, Liu Z, Shi M, Zhao P, Fu B, Zhang Z, Yang H, Zhang H, Zhou C, Yao J, Jin L, Wang H, Yang Y, Fu YX, Wang FS. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology. 2007 Jun;132(7):2328-39.

[7] Serr I, Kral M, Scherm MG, Daniel C. Advances in Human Immune System Mouse Models for Personalized Treg-Based Immunotherapies. Front. Immunol. 2021 Feb 18;12:643544.

[8] Li Y, Strick-Marchand H, Lim AI, Ren J, Masse-Ranson G, Dan Li, Jouvion G, Rogge L, Lucas S, Bin Li, Di Santo JP. Regulatory T cells control toxicity in a humanized model of IL-2 therapy. Nat. Commun. 2017 Nov 24;8(1):1762.

 

Tags: Humanized Models