The generation of HR-deficient spectrum genotypes is shown in Fig. To produce transformed murine fallopian tube epithelial (m-FTE) cells bearing patient-relevant mutant genotypes, we identified the most common combinations of mutations observed in HR-deficient spectrum and HR-proficient spectrum HGSC patient samples listed in the TCGA data set (Supplementary Fig. Given the unrealized potential of ICB and resistance to current therapies in HGSC, models such as these could reveal novel treatment strategies and identify therapeutic targets to improve women's response rates under treatment. These proof-of-concept preclinical models allowed us to characterize certain mutational spectra's influence on the tumor-immune microenvironment and test new combinations of standard therapies and immunotherapies. We introduced them into Trp53 −/− or Trp53 −/− Brca1 −/− mutant ( 20) FTE cells of C57BL/6 mice using the CRISPR/Cas9 methodology to introduce biallelic deletions and/or lentiviral or retroviral gene transduction to model overexpression. We selected the most common combinations of co-occurring mutations observed in the HR-deficient (HRD) spectrum and the HR-proficient (HRP) spectrum HGSC patient samples from The Cancer Genome Atlas (TCGA). Herein, we generated genetically distinct HGSC cell line models bearing genetic alterations representing human tumors and that can be propagated in fully immunocompetent, syngeneic mouse hosts. Moreover, such models lack the flexibility to control the timing of tumor outgrowth, rendering them less suitable as preclinical models. 14–17) have been developed, including those derived from fallopian tube epithelial (FTE) cells-the presumed normal cells of origin of HGSCs ( 17–19) although useful, complex combination genotypes are laborious to construct via crosses between germline mutation–bearing mouse strains. Over the years, several genetically engineered transgenic mouse models (GEMM refs. Nonetheless, the ID8 model does not carry the common mutations and somatic copy-number alterations observed in human HGSCs ( 12). In contrast, syngeneic models, such as the commonly used ID8 murine model ( 11), together with genetically modified versions of these cells ( 12, 13), have been extensively used to investigate the roles of the immune system in HGSC progression and to study therapeutic responses. These data provide proof of concept that our models can identify new immunotherapy targets in HGSC.Ĭurrently used models to study HGSC include patient-derived xenografts growing in immunodeficient hosts, limiting the study of tumor–immune interactions ( 10). These lines form tumors recapitulating human disease, including genotype-driven responses to treatment, and enabled us to identify follistatin as a driver of resistance to checkpoint inhibitors. For homologous recombination–proficient tumors, we constructed genotypes combining loss of Trp53 and overexpression of Ccne1, Akt2, and Trp53 R172H, and driven by KRAS G12V or Brd4 or Smarca4 overexpression. We transformed murine-fallopian tube epithelial cells to phenocopy homologous recombination–deficient tumors through a combined loss of Trp53, Brca1, Pten, and Nf1 and overexpression of Myc and Trp53 R172H, which was contrasted with an identical model carrying wild-type Brca1. We developed a series of mouse models that carry genotypes of human HGSCs and grow in syngeneic immunocompetent hosts to address this gap. ![]() Despite advances in immuno-oncology, the relationship between tumor genotypes and response to immunotherapy remains poorly understood, particularly in high-grade serous tubo-ovarian carcinomas (HGSC).
0 Comments
Leave a Reply. |