ideasIdea
Map which tumour clones sit next to which immune cells before choosing therapy
New imaging shows where every cell type sits in a tumour slice. Using it to see which sub-populations are hidden from immune cells could explain why immunotherapy fails in parts of a tumour.
Spatial transcriptomics and multiplex imaging can now assign genotype-inferred clones and immune phenotypes to positions in a section. The proposal is a diagnostic-biopsy pipeline reporting clone-immune neighbourhoods: which subclones are immune-excluded, which express MHC, and whether resistant clones cluster in immune deserts. This would be used to decide whether to combine a targeted agent with immunotherapy or a stroma-modifying agent.
Hypothesis
Tumours in which the dominant resistant subclone occupies an immune-excluded niche progress on immunotherapy combinations at a higher rate than tumours with immune-infiltrated resistant subclones, and this is measurable at baseline.
Rationale
Heterogeneity is spatial as well as genetic; immune exclusion is a local property. Current bulk PD-L1 or TMB scores erase both dimensions.
What would test it
Retrospective spatial profiling of 200 pre-treatment biopsies from immunotherapy trials with known outcomes; prospective validation if the neighbourhood score adds to PD-L1 and TMB.
Maturity
preclinical evidence
Who has to act
research
Cost to try
Medium ($1M to $50M)
Years to first evidence
4
Bottlenecks it attacks
- Tumour heterogeneity and clonal evolution · A tumour is many tumours. Treatments that kill most cells leave the rest to grow back, changed.
- No one can predict who responds to immunotherapy · Checkpoint drugs cure some patients and do nothing for most. We still cannot tell the two apart before treating.