Effective allogeneic natural killer cell therapy for pancreatic adenocarcinoma avails conserved activating receptors and evades HLA I-driven inhibition

Abstract

BackgroundAt diagnosis, [~]80% of pancreatic ductal adenocarcinomas (PDAC) have metastasized. Relapse is thus common even among patients that undergo surgical resection, the only curative option. PDAC progresses rapidly, and existing immunotherapies have been ineffective. We hypothesized that natural killer (NK) cell immunotherapies could be effective against PDAC because they recognize conserved and heterogeneous features associated with cellular stress and transformation, and can seek out metastases distal to the primary tumour site. Here, we aim to define the key features of NK cells as effective agents for PDAC immunotherapy. MethodsWe used TCGA PDAC Firehose data and flow cytometry to predict and measure the most common activating or inhibitory ligands available on PDAC for NK cell activation. To ascertain how the tumour might alter expression of these ligands during treatment, inflammation or immune pressure, we measured expression of NK ligands at rest, or after exposure to immune cells or inflammation. To test and rank the functional importance of these dynamic ligands in the recognition, killing and control of PDAC View larger version (47K): org.highwire.dtl.DTLVardef@f6ed8forg.highwire.dtl.DTLVardef@1667904org.highwire.dtl.DTLVardef@9330ccorg.highwire.dtl.DTLVardef@168c85a_HPS_FORMAT_FIGEXP M_FIG C_FIG