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

Dr Andrew Futreal

Chair ad interim of the Department of Genomic Medicine

University of Texas, MD Anderson Cancer Center, Houston, TX, USA

Collaborator

Dr Jorge Reis-Filho

Memorial Sloan Kettering Cancer Center, New York, USA