Abstract A26: Humanized mouse model: A model to understand mechanisms of immune non-responsiveness to immune checkpoint inhibitors in melanoma

Abstract

Abstract Immune checkpoint inhibitor therapy (anti-CTLA4 or anti-PD1 antibodies) is rapidly emerging as a front-line treatment option for many solid tumors. However, only a third of melanoma patients respond to immune checkpoint blockade. Currently available mouse xenograft and transgenic models have many shortcomings and are unable to address the basis of therapy resistance and immune nonresponsiveness that are observed in patients. Thus, there is an urgent need to establish an in vivo model with a human immune microenvironment that can address issues of therapy resistance. Our laboratory has developed a novel humanized mouse melanoma model. Immunodeficient NSG mice were reconstituted with human CD34+ cells and after 8-12 weeks, mice are fully reconstituted with human innate (monocyte/myeloid lineage cells, dendritic cells and NK cells) and adaptive (T and B cells) immune cells. Humanized mice were then challenged with HLA-matched melanoma cells, and the functional ability of human immune cells to restrict tumor growth was monitored. Delayed tumor growth was observed in humanized mice, indicating in vivo sensitization of human immune cells to melanoma. This was confirmed by in vitro demonstration of human lymphocytes from tumor-bearing mice showing enhanced cytokine expression after stimulation with melanoma antigen peptides. In therapy studies, tumor-bearing humanized mice treated with anti-PD-1 showed restricted tumor growth. Anti-PD-1 therapy resulted in enhanced infiltration of T cells that correlated with tumor response. MassCyTOF studies were performed using a panel of immune markers to understand the mechanism of therapy nonresponsiveness in some tumors. Downmodulation of HLA-class I molecules and increased presence of FOXP3+ cells in the tumor region were seen. Our results suggest that humanized mouse melanoma model can be explored further to understand the causes of therapy resistance and immune nonresponsiveness. Citation Format: Rajasekharan Somasundaram, Anastasia Samarkina, Thomas Connelly, Robin Choi, Hedy Choi, Kar Muthumani, Xiaowei Xu, Klaus Kaestner, Meenhard Herlyn. Humanized mouse model: A model to understand mechanisms of immune non-responsiveness to immune checkpoint inhibitors in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A26.