Discovery of novel immune-regulatory mechanisms through spatial and functional characterization of immune cells and PDGFR-defined subsets of fibroblasts

Analyses of pre-clinical cancer models imply immune-regulatory roles of cancer-associated fibroblasts (CAFs). PDGFRs are emerging as functionally and clinically relevant CAF subset markers. These findings strongly support analyses of potential immune-modulatory roles of PDGFR-defined CAF subsets.

The overall aim of this project is to identify and molecularly define clinically relevant tumor immune-modulatory pathways involving paracrine niche-like signaling between immune cells and PDGFR-defined subsets of fibroblasts.Sub-study 1 aims to identify new niches composed of specific combinations of fibroblast and immune cell subsets.

This will be achieved through high-content analyses of clinical samples using multiplex stainings subjected to digital-image-analyses.Sub-study 2 aims to validate mechanistic importance of candidate niches from sub-study 1 by searching for outcome associations through analyses of multiple well-annotated breast cancer cohorts.Sub-study 3 aims to use cell and animal model studies to define molecular details of the  immune-modulatory signaling that functionally underlie the outcome associations of the novel fibroblast/immune  niches.

Studies are supported by a set of original published and preliminary findings from applicant. A defining feature in the study is the use of multiplex profiling of clinical samples as a discovery approach. Ultimately, studies should define novel immune-regulatory mechanisms with cancer biomarker and drug-target potential.