Immune humanized mice reconstituted with peripheral blood mononuclear cells or hematopoietic stem cells develop distinct MDA-MB-231 tumor immune microenvironments

Abstract

Triple-negative breast cancer (TNBC) is one of the most fatal subtype of breast cancer. Tumor immune microenvironments (TIMEs) have critical influences on TNBC therapies. However, syngeneic mouse tumor models are insufficient to evaluate immunotherapeutic efficacy, because the different immune responses between mice and human. Therefore, human xenograft tumor mouse models with humanized immune systems (HIS) are more suitable for evaluation of immunotherapeutic efficacy. In these study, two immune humanized mouse models transferred with human hematopoietic stem cells (hHSC-HIS) or human peripheral mononuclear cells (hPBMC-HIS) in our advanced severe immune deficiency (ASID) mice were generated. Both systemic immune profiling and TIMEs of TNBC MDA-MB-231 tumors from hHSC- and hPBMC-HIS ASID models were compared. Generation of the comprehensive human immune system and large amounts of human macrophages/bone marrow-derived stromal cells around the TIMEs were noted in hHSC-HIS ASID mice, but the growth of TNBC was not affected. In contrast, T cells dominated the systemic immune system and TIMEs in hPBMC-HIS ASID mice, and inhibited the tumor growth. In summary, the TIMEs of hHSC-HIS ASID model is suitable for validations of immunotherapies reversing immune suppression. The TIMEs of hPBMC-HIS ASID can be applied for cytotoxicity test of tumor specific T cells.