Our Science

A NEW ROLE FOR FIBROBLASTS

We are developing first-in-class therapies that interrupt pathological fibroblast-driven immune signalling.

In healthy tissue, fibroblasts maintain tissue structure and coordinate normal processes such as wound healing. Previously fibroblasts were thought to be bystanders in certain diseases, however recent data point to a key role for fibroblasts in driving and maintaining disease in cancer and inflammatory disease.

Using state-of-the-art single cell technology, Mestag’s Founders identified pathogenic populations of fibroblasts that appear to act as “immune sentinels” and influence both the innate and adaptive immune responses. Landmark studies have shown that certain fibroblast populations may sustain and propagate chronic inflammation in inflammatory disease, whilst in cancer, they may play an active role in excluding immune cells from entering the tumour nests, shielding the tumour from the immune system.

DEFINING DISEASE-DRIVING FIBROBLAST POPULATIONS

Powerful single cell analyses enable us to look at fibroblasts with exquisite precision, revealing subpopulations with diverse functionality.

Analysis of disease tissues identifies activated fibroblasts that map into distinct populations with defined characteristics. These populations appear to be conserved across species, organs and disease contexts and may have specific functions in influencing the body’s immune response. Disease-associated fibroblast populations we are interested in include:

  • Inflammatory Fibroblasts: Release chemokines and cytokines to recruit and educate immune cells
  • Myofibroblasts: Shape the tissue microenvironment via matrix production and remodelling

  • Fibroblast Reticular Cells: Initiate and organise lymphoid structures and provide support and education for immune cells

Image thanks to Dr Jenny Marshall and Dr Triin Major.

OUR OPPORTUNITY

To interrupt pathological fibroblast-driven immune signalling across diseases.

In oncology, our focus us on activating and/or providing immune cell access to the tumour to overcome immune exclusion.

In inflammatory disease we aim to reduce a chronic inflammatory state, restore the balance of fibroblast quiescence (vs activation), and impact clinically-relevant endpoints such as mucosal healing.

 

Zhang et al, Nature Imm 2019
Elyada et al, Cancer Discov, 2019
Wang et al, Nature Comm, 2018
Croft et al, Nature 2019
Korsunsky et al, Nature, 2021
Qian et al, Cell Research, 2020
Desbois et al, Nature Comms, 2020
Buechler et al, Nature, 2021

FIBROBLASTS. REIMAGINED.