Abstract
Immunotherapy is one of the most promising cancer treatment modalities, but the lack of appropriate preclinical in vivo models hampers the development of novel immunotherapeutic strategies. Here, we studied the ability of transplanted human cancer cells to form primary tumors and metastasize in humanized immune system (HIS) mice created by transfer of CD34+ human hematopoietic stem cells. All tested transplanted cancer cell lines developed primary tumors that progressed nearly synchronously. Spontaneous lung and liver metastases developed from both orthotopic and ectopic transplanted cancer cells, and the ability to spread inversely correlated with the extent of CD8+ infiltration in the primary tumor. Further analysis revealed that interactions between the cancer model and the tumor‐infiltrating lymphocytes created tumor microenvironments (TMEs) resembling clinical cancers. Some models were largely immune cell‐excluding, while others appeared to develop adaptive resistance to immune‐mediated destruction by increased expression of programmed death ligand 1 (PDL1) and recruitment of human regulatory T cells. Our data suggest that HIS mice may provide a promising in vivo tumor model for evaluating immune modulatory anticancer therapies. Moreover, our study identified different tumor models resembling specific types of human TMEs, rendering each beneficial for addressing disease‐specific issues.
Highlights
Metastases remain a major clinical challenge, accounting for more than 90% of cancer-related deaths (Hanahan and Weinberg, 2011)
Human xenograft mouse models are used for translational cancer research and oncology drug development, but the immunodeficiencies of these conventional models restrict their use for development of immunotherapies and other treatments in which the interplay with the immune system influences the Abbreviations BALB/c Rag2À/À IL2RccÀ/À SIRPa.NOD (BRGS), BALB/c Rag2À/À IL-2RccÀ/À SIRPa.NOD; EGFR, epidermal growth factor receptor; FoxP3, forkhead box protein P3; HIS, humanized immune system; HSC, hematopoietic stem cells; IHC, immunohistochemistry; PD1, programmed death 1; PDL1, programmed death ligand 1; TIL, tumor-infiltrating lymphocyte; TME, tumor microenvironments; Tregs, regulatory T cells
After orthotopic or ectopic transplantation of cancer cells, tumors developed on both left and right sides of all HIS mice transplanted with the two human triplenegative breast cancer cell lines, MDA-MB-231 (5/5 mice) and MDA-MB-468 (5/5 mice), and the human melanoma cell line A375 (6/6 mice), demonstrating that the presence of the allogeneic human immune system did not prohibit primary tumor development
Summary
Metastases remain a major clinical challenge, accounting for more than 90% of cancer-related deaths (Hanahan and Weinberg, 2011). While it is encouraging that immunotherapy, immune checkpoint inhibitors, has recently improved overall survival of patients with certain types of cancer (Brahmer et al, 2012; Herbst et al, 2014; Hodi et al, 2010; Powles et al, 2014; Topalian et al, 2012), its effectiveness is limited to a small patient subpopulation. Human xenograft mouse models are used for translational cancer research and oncology drug development, but the immunodeficiencies of these conventional models restrict their use for development of immunotherapies and other treatments in which the interplay with the immune system influences the Abbreviations BRGS, BALB/c Rag2À/À IL-2RccÀ/À SIRPa.NOD; EGFR, epidermal growth factor receptor; FoxP3, forkhead box protein P3; HIS, humanized immune system; HSC, hematopoietic stem cells; IHC, immunohistochemistry; PD1, programmed death 1; PDL1, programmed death ligand 1; TIL, tumor-infiltrating lymphocyte; TME, tumor microenvironments; Tregs, regulatory T cells.
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