Human cancer evolution in the context of a human immune system in mice

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.

RX-5902, a novel β-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast Cancer

“…In dosing studies, we found that in both models, RX-5902 demonstrated anti-tumor activity on its own but this was significantly enhanced when combined with checkpoint inhibitors. The tumors in the hu-CB-BRGS MDA-MB-231 bearing mice were well-infiltrated with human immune cells, unlike other “cold” tumors we and others have observed with the use of this model [ 18 , 33 ]. The major infiltrates are T cells and myeloid cells, with very few B cells consistent with other reports [ 18 , 34 ].…”

Immunotherapies and Metastatic Cancers: Understanding Utility and Predictivity of Human Immune Cell Engrafted Mice in Preclinical Drug Development

“…However, these percentages are not universal and the amount of immune cells in the mice depends at least on the age and strain of the mice, the method used to cause myelosuppression, the type of donor material and route and number of injected cells. In these models, T cells home to thymus where they mature to CD4+ or CD8+ cells and then travel to other lymphoid organs [88]. Importantly in the context of oncology, the matured CD8+ cells can inhibit tumor growth when the mice are treated with an immunotherapeutic agent [88].…”

“…In these models, T cells home to thymus where they mature to CD4+ or CD8+ cells and then travel to other lymphoid organs [88]. Importantly in the context of oncology, the matured CD8+ cells can inhibit tumor growth when the mice are treated with an immunotherapeutic agent [88].…”

“…Development of metastases in humanized mice has mostly been monitored only from subcutaneous and orthotopic cancer cell injection models. Generally, it is thought that tumor growth, especially in subcutaneous models, does not vary if the models are performed in immunodeficient or humanized models [88]. Still, the situation might change dramatically in the context tumor type [87] or when performing studies in metastasis models [92].…”

“…Gammelgaard and colleagues studied the growth and metastasis of human melanoma A375 cell line and two human triple-negative breast cancer (TNBC) cell lines, MDA-MB-231 and MDA-MB-468 in CD34+ HSC transplanted BRGS mice [88]. In their study, metastases were monitored after surgical removal of primary tumors reaching the maximum size.…”