PRECISION is funded by Cancer Research UK and Dutch Cancer Society
WORKPACKAGE 3
Characterization of the role of the immune microenvironment as a determinant of DCIS clinical biology
Hypothesis-driven questions
- the immune microenvironment is a key determinant of risk for DCIS progression and a markedly ‘active’ immune signature is associated with highest risk lesions.
- T-cell receptor (TCR) clonality and neo-antigen burden will serve as covariates to risk of progression.
- assuming high risk lesions can be reliably identified via their immune microenvironment signatures, there are immune-oncology targets that recommend themselves for therapeutic intervention to mitigate invasive disease.
Key lines of investigation will be leveraging highly annotated sample series comprised of three main phenotypic groups:
- Primary DCIS with invasive recurrence and matched invasive recurrence
- Primary DCIS with DCIS recurrence and matched DCIS recurrence
- DCIS without recurrence
Sampling of cases from each group with full overlap of cases being investigate in WP2 will provide the most detailed molecular characterisation of DCIS to date. A further line of investigation will be to assess the potential interplay of genomic and immune heterogeneity, particular as this relates to potential neo-antigen burden, T-cell receptor repertoire and diversity and quantitative assessment of immune infiltrates and expression of microevironmental genes. Lastly, if a markedly high risk group is identified, further detailed analysis of potential targets for therapeutic intervention, particularly from an immune-oncology perspective will be explored.
Workpackage 3 is responsible for the project objective to identify key determinants of DCIS clinical phenotypes and their provision for biomarker driven assays for risk stratification and early immune-oncology treatments in high risk DCIS
Milestones
| 3.1 | Ground breaking subcellular detail on key proteins implicated by WP3 analyses and the other Precision WPs in the tumor microenvironment utilizing state-of-the-art imaging mass cytometry from FFPE material |
| 3.2 | High resolution Nanostring expression datasets and analyses of custom immune microenvironment and industry-standard cancer pathway codesets |
| 3.3 | Generation of and analyses of T-cell receptor diversity data coupled with analyses of predicted neo-antigen burden |
| 3.4 | Comprehensive multiplex IF datasets and analyses of the immune microenvironment of DCIS from indolent, recurrent and recurrent/invasive disease |
| 3.5 | Integrated analyses of these data with emphasis on correlations/prognostic capability for DCIS clinical phenotypes |
WP lead
Prof. Dr. Andrew Futreal
Chair/Professor
UT MD Anderson Cancer Center, USA
Co-I
Dr. Nicholas E. Navin
Department of Genetics
Department of Bioinformatics
Director, CPRIT Single Cell Genomics Center
Co-Director, DNA Sequencing Core
UT MD Anderson Cancer Center, USA
Collaborator
Dr Jorge Reis-Filho
Memorial Sloan Kettering Cancer Center, New York, USA