{"entity":{"id":"idea-immune-exclusion-drivers","kind":"idea","name":"What actually holds T cells at the tumour border?","aka":[],"tldr":"In immune-excluded tumours T cells reach the border but cannot get in, held back by fibroblasts, matrix, abnormal vessels, CXCL12 gradients or myeloid cells, and TGF-β drugs on their own have failed. If single-cell and spatial profiling can show which stromal programme dominates in each tumour, matching the drug (TGF-β, FAP, CXCR4 or VEGF) to it could let immunotherapy work.","summary":"This open question asks what actually holds T cells at the tumour border: in immune-excluded tumours the immune cells are present but cannot get in, and knowing the dominant barrier would open the gate. Fibroblasts, matrix, abnormal vessels, CXCL12 gradients and myeloid cells are all implicated, yet TGF-β-directed drugs failed as monotherapy, suggesting redundancy or wrong patient selection. The hypothesis is that a few stromal programmes, classifiable by Single-cell & spatial profiling, drive Immune exclusion, so matching the agent (TGF-β, FAP, CXCR4 or VEGF) to the programme converts excluded tumours into inflamed ones. The test is a biomarker-stratified window trial with PD-1 blockade, and the idea links to FAPI PET and Hot vs cold tumours.","asOf":"2026-09-08","links":[{"label":"Mariathasan et al., TGF-beta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells (Nature 2018)","url":"https://doi.org/10.1038/nature25501"}],"tags":["mechanism","open-question"],"related":[],"cancers":[],"sections":[],"technologies":["single-cell-spatial","fapi-pet","checkpoint-inhibitor"],"targets":["fap","vegf","pd1"],"drugs":[],"companies":[],"institutions":["gustave-roussy","mskcc","institut-curie"],"pathways":["tumor-microenvironment","tgf-beta","pd1-checkpoint"],"terms":["immune-exclusion","cold-vs-hot"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-mariathasan-nature"],"journals":[],"dependsOn":[],"notes":[],"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.","test":"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"},"route":"/ideas/idea-immune-exclusion-drivers/","neighbours":{"technology":[{"id":"fapi-pet","kind":"technology","name":"FAPI PET","route":"/technologies/fapi-pet/"},{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"single-cell-spatial","kind":"technology","name":"Single-cell & spatial profiling","route":"/technologies/single-cell-spatial/"}],"target":[{"id":"fap","kind":"target","name":"FAP","route":"/targets/fap/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"vegf","kind":"target","name":"VEGF / VEGFR","route":"/targets/vegf/"}],"institution":[{"id":"gustave-roussy","kind":"institution","name":"Gustave Roussy","route":"/institutions/gustave-roussy/"},{"id":"institut-curie","kind":"institution","name":"Institut Curie","route":"/institutions/institut-curie/"},{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"}],"pathway":[{"id":"pd1-checkpoint","kind":"pathway","name":"PD-1 / PD-L1 immune checkpoint & T-cell activation","route":"/pathways/pd1-checkpoint/"},{"id":"tgf-beta","kind":"pathway","name":"TGF-β signalling","route":"/pathways/tgf-beta/"},{"id":"tumor-microenvironment","kind":"pathway","name":"Tumour microenvironment (TME)","route":"/pathways/tumor-microenvironment/"}],"term":[{"id":"cold-vs-hot","kind":"term","name":"Hot vs cold tumours","route":"/terms/cold-vs-hot/"},{"id":"immune-exclusion","kind":"term","name":"Immune exclusion","route":"/terms/immune-exclusion/"}],"paper":[{"id":"paper-mariathasan-nature","kind":"paper","name":"TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells","route":"/key-papers/paper-mariathasan-nature/"}]}}