Development of a Non-small cell lung cancer PDX model in a myeloid-boosted humanized host highlights a M2 polarization phenotype within the myeloid compartment
Despite immunotherapy advancing the way Non-Small Cell Lung Cancer (NSCLC) patients are treated in the clinic, patient outcome is still unpredictable. The tumor microenvironment (TME) plays a central role in early establishment, progression, and metastasis in NSCLC. Specifically, intrinsic TME factors can lead to inflammatory or immune-suppressive phenotypes. Innate immunity and particularly the macrophage population influences TME behavior. Macrophages in non-responsive patients are polarized towards the M2-type, which is known to dampen the immune response by secreting anti-inflammatory factors including IL-10 and TGF-β2. Given the central role of macrophages in modulating the TME in NSCLC patients, it becomes important to leverage model systems in which macrophage phenotype recapitulates the TME composition of NSCLC patients.
Syngeneic models are characterized by their murine immune system which is very different from the human system. Thus, these models are not ideal to study the human immune response to various therapeutics nor to study the human cellular interaction within the TME. Intrinsic tumor heterogeneity is one of the main factors driving tumor progression and response. For this reason, immortalized cell lines are not an ideal system to represent the diversity of the patient population.
To dissect the mechanism underlying immunosuppression in cancer, we need to combine two clinically relevant platforms: a patient-derived xenograft (PDX) model which represents the necessary human tumor heterogeneity; a humanized model that reliably recapitulates the complexity and functionality of the human myeloid compartment. These two requirements within the same model overcome species-specific limitations and compensate for tumor heterogeneity.
Champions Oncology partnered with TransCure BioServices to generate an NSCLC PDX model implanted in a mouse host reconstituted with a human functional immune system. This platform enhances human myeloid cell engraftment through a physiological boost of human cytokines.