Humanized mice in studying efficacy and mechanisms of PD‐1‐targeted cancer immunotherapy

Abstract

Establishment of an in vivo small animal model of human tumor and human immune system interaction would enable preclinical investigations into the mechanisms underlying cancer immunotherapy. To this end, nonobese diabetic (NOD).Cg-PrkdcscidIL2rgtm1Wjl/Sz (null; NSG) mice were transplanted with human (h)CD34+ hematopoietic progenitor and stem cells, which leads to the development of human hematopoietic and immune systems [humanized NSG (HuNSG)]. HuNSG mice received human leukocyte antigen partially matched tumor implants from patient-derived xenografts [PDX; non–small cell lung cancer (NSCLC), sarcoma, bladder cancer, and triple-negative breast cancer (TNBC)] or from a TNBC cell line-derived xenograft (CDX). Tumor growth curves were similar in HuNSG compared with nonhuman immune-engrafted NSG mice. Treatment with pembrolizumab, which targets programmed cell death protein 1, produced significant growth inhibition in both CDX and PDX tumors in HuNSG but not in NSG mice. Finally, inhibition of tumor growth was dependent on hCD8+ T cells, as demonstrated by antibody-mediated depletion. Thus, tumor-bearing HuNSG mice may represent an important, new model for preclinical immunotherapy research.—Wang, M., Yao, L.-C., Cheng, M., Cai, D., Martinek, J., Pan, C.-X., Shi, W., Ma, A.-H., De Vere White, R. W., Airhart, S., Liu, E. T., Banchereau, J., Brehm, M. A., Greiner, D. L., Shultz, L. D., Palucka, K., Keck, J. G. Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy.

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

“…In our hands, the MDA‐MB‐231 model exhibited a typical type I TME with high levels of TILs driving upregulation of PDL1 leading to adaptive resistance. This observation is consistent with the observed growth‐inhibitory effect of PD1 blockade in HIS mice (Wang et al ., ) and indicates that the MDA‐MB‐231 model may prove valuable for evaluating combination partners to PD1/PDL1 blockade, and possibly also treatments directed toward relieving the immune suppressive capacity of human Tregs. It is noteworthy that another group recently reported no effect on MDA‐MB‐231 PDL1 expression when transplanted subcutaneously in HIS mice (Rom‐Jurek et al ., ).…”

“…Previous studies in HSC‐transplanted NSG mice have reported primary tumor development, but with the exception of the study by Wang et al . (), the growth pattern was either not illustrated or largely heterogeneous (Rongvaux et al ., ; Schilbach et al ., ; Wege et al ., ). The apparent cancer tolerance in BRGS‐HIS mice was not only due to an overwhelming growth rate, since the slow‐growing MDA‐MB‐468 tumors were not rejected.…”

“…We found selective accumulation of immune cells at tumor sites, but not in normal tissues. Similar to clinical breast cancers (Savas et al ., ) and consistent with previous reports of triple‐negative breast cancer growth in HIS mice (Wang et al ., ), CD4+ T cells were the major infiltrating TIL subpopulation, with CD8+ T cells accounting for ~ 20–30%. Importantly, there was no correlation between the number of reconstituted immune cells in the blood and within the tumor beds, indicating selection and proliferation of tumor‐reactive immune cells followed by homing to the tumor bed.…”

“…Intriguingly, it was very recently demonstrated that allogeneic tumors grow at a comparable pace in immune-deficient and HIS mice. Furthermore, the authors showed that reconstituted immune cells were infiltrating transplanted tumors, and were able to delay tumor growth in a CD8+ T cell-dependent manner when treated with a programmed death 1 (PD1) inhibitor (Wang et al, 2018). Building on these reports, we examined whether three well-characterized human cancer cell lines [A375 (melanoma), and MDA-MB-231 and MDA-MB-468 (both triple-negative breast cancer)] were able to develop primary tumors and distant metastasis in HIS mice.…”

Personalized Cancer Therapy Prioritization Based on Driver Alteration Co-occurrence Patterns

“…Although PDXs have shown a good level of agreement with the course of disease evolution and treatment response observed in the tumors in the patient [30-33, 84, 85], they present some important drawbacks, such as the eventual loss of intratumoral heterogeneity [86,87] or certain engraftment bias [30,88]. Additionally, we have to consider that PDXs might not completely recapitulate the influence of the tissue of origin in tumors that have been implanted subcutaneously in immunodeficient mice and whose stroma has possibly regressed and/or been replaced by mouse stroma, altering thus their sub-clonal evolution and response to treatments [84,89]. However, our strategy can be readily adapted to derive drug-response models from continuous clinical outcome measures, such as progression free survival, which better represent the data acquired during routine clinical practice and in clinical trials.…”