OnCo
ideasIdea

What actually holds T cells at the tumour border?

In many tumours the immune cells are present but cannot get in. If we knew the dominant barrier, we could open the gate and make immunotherapy work for more people.

TGF-β-activated fibroblasts, ECM density, abnormal vasculature, CXCL12 gradients, and myeloid cells are all implicated; TGF-β-directed drugs have failed as monotherapy, suggesting redundancy or wrong patient selection.

Hypothesis
Immune exclusion is driven by a small number of stromal programmes that can be classified from spatial profiling, and matching the anti-stromal agent to the programme (TGF-β vs FAP vs CXCR4 vs VEGF) converts excluded tumours to inflamed ones.
Rationale
Mariathasan 2018 and Tauriello 2018 showed TGF-β causality in models; spatial atlases show distinct exclusion architectures; FAP theranostics and CXCR4 antagonists reach the clinic.
What would test it
Biomarker-stratified window-of-opportunity trial: spatial transcriptomic classification of excluded tumours, randomise to matched stromal agent plus PD-1 versus PD-1 alone, primary endpoint change in intratumoural CD8 density.
Maturity
early clinical

Connected

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