Modeling the Tumor Microenvironment and Cancer Immunotherapy in Next-Generation Humanized Mice

Abstract

Cancer immunotherapy has brought significant clinical benefits to numerous patients with malignant disease. However, only a fraction of patients experiences complete and durable responses to currently available immunotherapies. This highlights the need for more effective immunotherapies, combination treatments and predictive biomarkers. The molecular properties of a tumor, intratumor heterogeneity and the tumor immune microenvironment decisively shape tumor evolution, metastasis and therapy resistance and are therefore key targets for precision cancer medicine. Humanized mice that support the engraftment of patient-derived tumors and recapitulate the human tumor immune microenvironment of patients represent a promising preclinical model to address fundamental questions in precision immuno-oncology and cancer immunotherapy. In this review, we provide an overview of next-generation humanized mouse models suitable for the establishment and study of patient-derived tumors. Furthermore, we discuss the opportunities and challenges of modeling the tumor immune microenvironment and testing a variety of immunotherapeutic approaches using human immune system mouse models.

The challenge of making the right choice: patient avatars in the era of cancer immunotherapies

“…To evaluate novel immunotherapies and identify biomarkers, humanized patient-derived xenografts (hPDX) are an important platform ( 86 – 92 ). Meanwhile, more than 45 PDX models are available including NSG, NOD-scid, NRG, BRGS, SRG and next-generation humanized mice ( 86 , 89 ). Besides therapeutic responses, possible side effects as well as tumor progression and metastasis can be studied in these whole organism models.…”

“…Of note, PBMC-engrafted mice can undergo a switch in immune cellular composition within 7 days. As a result, T cells might dominate and concomitantly myeloid as well as B and NK cells are underrepresented ( 89 ) thereby not fully representing the immune system of patients. Alternatively, engraftment can be achieved by CD34+ human hematopoietic stem cells to study immunotherapies in hPDX ( 91 , 102 , 103 ).…”

“…An important limiting factor of hPDX as patient avatar is the generation duration of months up to a year ( 91 ) depending on tumor entity, technology and mouse strain ( 89 ). In most cases, this time frame is not feasible to establish a patient avatar as co-clinical model as patient´s treatment must start within a short period of time (i.e.…”