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.

Breakthrough Discovery

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. Preliminary data suggest that lung apFibros help overcome resistance to checkpoint inhibitors.

Challenges to Overcome

For their immunotherapeutic exploitation of apFibros, two bottlenecks must be overcome:

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

Research Approach

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

Our goal is to dissect the molecular landscape that regulates fibroblast states. Ultimately, we aim to unravel perturbations that can diverge cancer-associated fibroblasts to antigen presenting states.

Core 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 the 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.