Loading
Mice with pancreatic cancer had tumour-specific T cells but did not respond to checkpoint drugs; the fibroblasts were coating the cancer cells with a chemical, CXCL12, that kept T cells away, and blocking it let the T cells in and made anti-PD-L1 work.
An autochthonous model of pancreatic ductal adenocarcinoma allowed analysis of why immunotherapy is ineffective. Despite cancer cell-specific CD8 T cells, mice did not respond to anti-CTLA-4 or anti-PD-L1. Depleting FAP-expressing carcinoma-associated fibroblasts achieved immune control and uncovered the antitumour effects of both checkpoint antagonists. T cells were absent from regions containing cancer cells, cancer cells were coated with CXCL12, and the FAP-positive CAF was the principal source of it. AMD3100, a CXCR4 inhibitor, induced rapid T-cell accumulation among cancer cells and acted synergistically with anti-PD-L1, leaving a residual tumour of premalignant epithelial and inflammatory cells.
The mechanistic account of T-cell exclusion that all later combination immunotherapy trials in pancreatic cancer cite, and the origin of CXCR4 inhibitor combinations.
Shares Immune exclusion, Cold tumours: immune deserts and exclusion, Hot vs cold tumours, PD-1 / PD-L1 immune checkpoint & T-cell activation.
Shares Hot vs cold tumours, CTLA-4, PD-1 / PD-L1 immune checkpoint & T-cell activation, PD-L1.
Shares Hot vs cold tumours, PD-1 / PD-L1 immune checkpoint & T-cell activation, PD-L1, Pancreatic ductal adenocarcinoma.
Shares David A. Tuveson, FAP, Fibroblast activation, desmoplasia & matrix stiffness, Pancreatic ductal adenocarcinoma.
Shares Hot vs cold tumours, CTLA-4, PD-1 / PD-L1 immune checkpoint & T-cell activation, Pancreatic ductal adenocarcinoma.
Shares Hot vs cold tumours, CTLA-4, PD-1 / PD-L1 immune checkpoint & T-cell activation, Pancreatic ductal adenocarcinoma.
Shares David A. Tuveson, Fibroblast activation, desmoplasia & matrix stiffness, Pancreatic ductal adenocarcinoma.
Shares Immune exclusion, FAP, Hot vs cold tumours, PD-1 / PD-L1 immune checkpoint & T-cell activation.