Artifying fibroblasts: Perturbation modelling in the lung tumor phase space to rewire fibroblasts for immunotherapy.

Introduction

Lung cancer is the leading cause of cancer death. Immunotherapy improved survival rates, but efficacy is limited to selected patients. We recently discovered universal antigen presenting fibroblasts (apFibros) across human and murine lung tumors and showed that they directly stimulate cancer-specific CD4 T cells, creating immunological hot spots that support immune rejection. These studies achieved a breakthrough on the role of in situ cancer antigen presentation and proposed a novel model whereby tumors can sustain T cells independently of lymph nodes.

Background

Preliminary data suggest that lung apFibros help overcome resistance to checkpoint inhibitors. For their immunotherapeutic exploitation of apFibros, two bottlenecks must be overcome:

1. Low numbers
2. Incomplete understanding of their configurations.

We will integrate computational and laboratory experiments and work in parallel in human and mouse models to generate perturbation datasets across single-cell/cell systems, transcriptomics/epigenomics, spatial/temporal levels, and dissect the molecular landscape that regulates fibroblast states. Our ultimate goal is to unravel perturbations that can diverge cancer-associated fibroblasts to antigen presenting states.

Research Questions

The following questions are at the core of our proposal:

i) How do diverse fibroblast states emerge and evolve?
ii) Which gene regulatory networks drive specificity of these states?
iii) Which are the functional modules that are driven by apFibros and how are they mechanistically explained?
iv) How can we transdifferentiate existing fibroblasts to acquire antigen presenting states?
v) How can fibroblast reprogramming help overcome immunotherapy resistance?

Conclusion

The proposed research should help advance mechanistic concepts in what we term the “adaptive immune mesenchyme,” decode the complexity of peripheral antigen presentation in tumors and beyond, and promote targeting of the stroma for immunotherapy.