ArticleBMC medicine2026
Extracellular matrix biomarkers of T-cell infiltration and tumor fibrosis predict response to nivolumab ± ipilimumab with SBRT in biliary tract cancer: insights from the CheckPAC trial.
Article in BMC medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02866383 (A Prospective Randomized, Open-label Phase 2 Study of Immune Checkpoint Inhibition, Nivolumab With or Without Ipilimumab in Combination With Radiation Therapy in Pretreated Patients With Metastatic Pancreatic Cancer or Biliary Tract Cancer.), which is not on this map. Cited by 1 paper.
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A Prospective Randomized, Open-label Phase 2 Study of Immune Checkpoint Inhibition, Nivolumab With or Without Ipilimumab in Combination With Radiation Therapy in Pretreated Patients With Metastatic Pancreatic Cancer or Biliary Tract Cancer.
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1 citing paper in PubMed.
- Mechanical properties of the tumor microenvironment: drivers of immunotherapy resistance in solid tumors.Frontiers in immunology · 2026Review
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8 authors.
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Abstract
backgroundBiliary tract cancer (BTC) is an uncommon malignancy with limited treatment options and poor prognosis. BTC is typically characterized by a desmoplastic, collagen-rich extracellular matrix (ECM), which has been linked to immune exclusion and therapy resistance. Although immune checkpoint inhibitors (ICI) combined with gemcitabine/cisplatin have become first-line treatment for advanced BTC, durable responses are rare, and predictive biomarkers for immunotherapy are lacking. We investigated the pharmacodynamic and predictive potential of liquid, ECM-derived biomarkers reflecting cytotoxic T-cell activity (granzyme B-degraded type IV collagen [C4G]) and fibrotic activity (pro-peptides of type III [PRO-C3] and VI [PRO-C6] collagens, matrix metalloprotease-degraded type I [reC1M], III [C3M], and IV collagens [C4M]) in patients with metastatic BTC receiving combined immunotherapy and radiotherapy.
methodsBiomarkers (C4G, PRO-C3, PRO-C6, reC1M, C3M, and C4M) were measured in serum from 61 patients with metastatic BTC enrolled in CheckPAC (NCT02866383), treated with stereotactic body radiotherapy (SBRT) combined with nivolumab (n = 19) or nivolumab/ipilimumab (n = 42). Biomarkers were assessed at baseline and day 60. Associations of baseline levels and on-treatment changes with overall survival (OS) and clinical benefit rate were evaluated; longitudinal analyses used a landmark approach.
resultsHigher baseline PRO-C3 and reC1M were associated with lack of clinical benefit (p < 0.05) and shorter OS (p < 0.05). In multivariable Cox regression adjusting for CA 19 - 9, ECOG performance status, and modified Glasgow Prognostic Score, PRO-C3 remained independently associated with OS. Longitudinally, C4G increased from baseline to day 60 in all patients with clinical benefit (p < 0.001), whereas no consistent changes were observed among patients without clinical benefit. For the landmark analyses, C4G increase was associated with clinical benefit (p = 0.007) and longer OS (p = 0.0045). Patients with low PRO-C3 and increased C4G at day 60 showed the most favorable survival, including a subgroup without RECIST-defined clinical benefit (p < 0.001).
conclusionsSerological biomarkers reflecting tumor fibrosis (PRO-C3) and cytotoxic T-cell infiltration (C4G) were associated with clinical benefit and OS and showed pharmacodynamic changes during therapy in patients with metastatic BTC treated with SBRT plus ICI. These biomarkers enable tracking of pharmacodynamic response to ICI, while independent validation is necessary to ensure their predictive utility in immunotherapy.
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