Evaluation of anti-PD-1-based therapy against triple-negative breast cancer patient-derived xenograft tumors engrafted in humanized mouse models

Abstract

BackgroundBreast cancer has been considered not highly immunogenic, and few patients benefit from current immunotherapies. However, new strategies are aimed at changing this paradigm. In the present study, we examined the in vivo activity of a humanized anti-programmed cell death protein 1 (anti-PD-1) antibody against triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) tumor models.MethodsTo circumvent some of the limitations posed by the lack of appropriate animal models in preclinical studies of immunotherapies, partially human leukocyte antigen-matched TNBC PDX tumor lines from our collection, as well as human melanoma cell lines, were engrafted in humanized nonobese diabetic/severe combined immunodeficiency IL2Rγnull (hNSG) mice obtained by intravenous injection of CD34+ hematopoietic stem cells into nonlethally irradiated 3–4-week-old mice. After both PDXs and melanoma cell xenografts reached ~ 150–200 mm3, animals were treated with humanized anti-PD-1 antibody or anti-CTLA-4 and evaluated for tumor growth, survival, and potential mechanism of action.ResultsHuman CD45+, CD20+, CD3+, CD8+, CD56+, CD68+, and CD33+ cells were readily identified in blood, spleen, and bone marrow collected from hNSG, as well as human cytokines in blood and engrafted tumors. Engraftment of TNBC PDXs in hNSG was high (~ 85%), although they grew at a slightly slower pace and conserved their ability to generate lung metastasis. Human CD45+ cells were detectable in hNSG-harbored PDXs, and consistent with clinical observations, anti-PD-1 antibody therapy resulted in both a significant reduction in tumor growth and increased survival in some of the hNSG PDX tumor lines, whereas no such effects were observed in the corresponding non-hNSG models.ConclusionsThis study provides evidence associated with anti-PD-1 immunotherapy against TNBC tumors supporting the use of TNBC PDXs in humanized mice as a model to overcome some of the technical difficulties associated with the preclinical investigation of immune-based therapies.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1037-4) contains supplementary material, which is available to authorized users.

Characterization of human cancer xenografts in humanized mice

“…3 6 Despite this, the use of antibodies against PD-1 has shown efficacy in human xenograft and patient-derived xenograft tumors in these mice, demonstrating that these cells can generate antitumor responses. [7][8][9][10] Whereas checkpoint modulators have shown antitumor activity in humanized mice, there are limited data reporting characterization on human immune cell subsets within these tumors. To this end, we characterized several commonly used xenograft models across a range of tumor types in CD34 + humanized non-obese diabetic-scid gamma (NSG) mice.…”

A mouse SWATH-MS reference spectral library enables deconvolution of species-specific proteomic alterations in human tumour xenografts

“…Mouse xenograft studies are one of the cornerstones of modern cancer research where human tumour cells are typically grafted into a mouse host either subcutaneously or orthotopically as a means to evaluate oncogene and tumour suppressor gene function or investigate the therapeutic effects of drugs [28, 29]. In these models, there are complex interactions between the human tumour cells and the host microenvironment which play important roles in driving cancer progression and therapy response [30–32].…”

‘Omics Approaches to Explore the Breast Cancer Landscape

“…Drawbacks for the use of PDXs include the selection of more aggressive cells within the patient sample and the use of immunocompromised mice to prevent tumor rejection. Developing mice with humanized immune systems can help to address this problem (Hasgur et al, 2016), as recently shown for a metastasis model (Rosato et al, 2018) (Figure 1D).…”