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