The FAP+ stromal cell establishes dominant immune suppression in an autochthonous model of pancreatic ductal adenocarcinoma


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Douglas Fearon1
1University of Cambridge, Cambridge, UK

Abstract

Clinical studies examining the effects of monoclonal anti-CTLA-4, -PD-1 and -PD-L1 prove that molecular interventions enhancing the function of T cells can reverse the growth of melanomas and certain adenocarcinomas.However, only a minority of patients had objective responses, and none with pancreatic ductal adenocarcinoma (PDAC) responded.One must conclude either that the majority of these cancers are inherently unresponsive to immunotherapies, or that an additional process dominates over these T cell-directed therapies.

Human adenocarcinomas contain a fibroblast-like stromal cell identifiable by the membrane protein, fibroblast activation protein-alpha (FAP). We reported in 2010 that conditionally depleting FAP+ cells from subcutaneous Lewis lung carcinomas expressing ovalbumin (LL2/OVA) caused immune control of tumour growth. Depleting FAP+ cells did not increase the number of peripheral OVA-specific CD8+ T cells, excluding an effect on T cell priming, so that relief from immune suppression explained the phenomenon.

We have now characterised the FAP+ stromal cell in the KPC model of autochthonous PDA. Transcriptomic analyses show that this FAP+ cell is identical to the carcinoma-associated fibroblast. As with the LL2/OVA tumour model, depleting FAP+ cells from PDAC rapidly led to slowing of PDAC growth, which depended on a pre-existing spontaneous immune response to cancer cells. Remarkably, the depletion of FAP+ cells also uncovered the anti-tumour effects of anti-CTLA-4 and anti-PD-L1, which were ineffective when given alone.Therefore, there is a hierarchy of tumoral immune suppression in PDAC, with that mediated by the FAP+ stromal cell dominating over at least two that directly affect the function of T cells. This conclusion implies that the full potential of clinical T cell immunotherapy of cancer may be achieved if immune suppression by the FAP+ stromal cell can be interrupted.