Abstract
Both targeted therapy and immunotherapy have been used successfully to treat melanoma, but the development of resistance and poor response rates to the individual therapies has limited their success. Designing rational combinations of targeted therapy and immunotherapy may overcome these obstacles, but requires assessment in preclinical models with the capacity to respond to both therapeutic classes. Herein, we describe the development and characterization of a novel, immunogenic variant of the BrafV600ECdkn2a−/−Pten−/− YUMM1.1 tumor model that expresses the immunogen, ovalbumin (YOVAL1.1). We demonstrate that, unlike parental tumors, YOVAL1.1 tumors are immunogenic in vivo and can be controlled by immunotherapy. Importantly, YOVAL1.1 tumors are sensitive to targeted inhibitors of BRAFV600E and MEK, responding in a manner consistent with human BRAFV600E melanoma. The YOVAL1.1 melanoma model is transplantable, immunogenic and sensitive to clinical therapies, making it a valuable platform to guide strategic development of combined targeted therapy and immunotherapy approaches in BRAFV600E melanoma.
Highlights
The development of targeted therapies and immunotherapies in recent years has revolutionized the landscape of cancer treatment, melanoma
Consistent with this, we found no significant difference in the growth kinetics or overall survival of YUMM1.1 tumors grown in immunocompetent C57BL/6 or immunodeficient NOD scid gamma (NSG) mice; which are T and B cell deficient and lack functional NK cells due to a null mutation in the IL-2 receptor common gamma chain (Fig. 1a)
We observed a significant increase in the frequency of major immune subsets, including CD8+ T cells, CD4+ T cells, T regulatory cells, NK cells, dendritic cells and macrophages, within YOVAL1.1 tumors compared to control YUMM1.1 and YV1.1 tumors (Fig. 2a and Supplementary Figs 2–4)
Summary
The development of targeted therapies and immunotherapies in recent years has revolutionized the landscape of cancer treatment, melanoma. The Yale University Mouse Melanoma (YUMM) series of cell lines can be efficiently grown and studied in immunocompetent C57BL/6 mice, and importantly, have been derived from genetically modified mice bearing mutations commonly found in human melanoma[19]. These models provide an immunocompetent and clinically relevant setting in which to study targeted and immune therapy combinations. As these lines were generated through the introduction of a small number of oncogenic driver mutations, they are poorly T www.nature.com/scientificreports/. Our data highlights the utility of YOVAL1.1 as a preclinical model for examining the complex interactions of targeted therapies and the immune system, providing a valuable platform to better guide clinical application of novel and existing therapy combinations in BRAFV600E melanoma
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