Abstract 1459: Patient-derived xenograft models of breast cancer with human immune components
Authors: Marlow Rebecca , Ilieva Kristina , Francesch Erika , Kyle Fernanda , Karagiannis Panagiotis , Hayday Adrian , Karagiannis Sophia , Tutt Andrew 
Published: August 2015

Breast cancer is a major cause of death in women in the UK and worldwide. It is now widely recognized that many cancers, including breast, elicit immune cell engagement resulting in immune responses directed against over-expressed or aberrantly presented antigens. A greater understanding of these interactions has had significant effects in improving the prognosis in other tumor types e.g. melanoma, but has not been extensively studied in breast cancer. Here we aim to build disease-relevant in vivo models of breast cancer that recapitulate the immune-tumor microenvironment found in patient tumors.

Patient-derived xenografts (PDX) are in vivo pre-clinical models derived from transplantation of patient tumor material into severely immunocompromised hosts. These models recapitulate major clinicopathologic features of patient tumors and represent the breadth of diversity in phenotype and genotype found across breast cancer. These PDX models can be studied in order to further our understanding of intrinsic tumor cell biology and response to treatment. However, as these tumor models are maintained in severely immunocompromised hosts, we cannot study the relevant interactions between tumor and immune cells. In order to address this, we have established humanized PDX models.

We have developed a humanized triple-negative breast PDX model in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. The experimental set-up is based on those successfully used to identify novel antibody-based therapeutic strategies in melanoma (Karagiannis et al 2013). The PDX tumor is established by orthotopic transplantation into the inguinal mammary fat pad. The host is then engrafted with human immune effector cells (peripheral blood lymphocytes (PBL) isolated from healthy volunteers). Following tumor development, host and tumor tissues are processed for flow cytometry and immunohistochemistry (IHC). We observe a ∼40% engraftment of human immune effector cells in host spleens following transplantation and tumor development by flow analysis. We also observe human CD45+ leukocyte populations in the tumor, blood and other organs. Tumor-infiltrated lymphocytes expressed the immune checkpoint phenotype of patient cancers. We are now investigating the subtypes of immune effector cells present our model, whether novel antibody-based therapies can be used to block tumor formation, and how immune checkpoint molecules are modulated. We are currently testing new PDX models for their capacity for humanization by immune effector cells.

Our over-arching aim is to determine whether these models can recapitulate immune responses directed against tumor antigens in order to study the mechanisms of action and efficacy of novel therapeutics to treat breast cancer. Humanized pre-clinical PDX models could be a feasible approach to accelerate therapeutic discovery relevant to impacting tumor and immune stromal interaction for patient benefit.

Citation Format: Rebecca Marlow, Kristina Ilieva, Erika Francesch, Fernanda Kyle, Panagiotis Karagiannis, Adrian Hayday, Sophia Karagiannis, Andrew Tutt. Patient-derived xenograft models of breast cancer with human immune components. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1459. doi:10.1158/1538-7445.AM2015-1459