RESUMO
PURPOSE: The molecular drivers of antitumor immunity in pancreatic ductal adenocarcinoma (PDAC) are poorly understood, posing a major obstacle for the identification of patients potentially amenable for immune-checkpoint blockade or other novel strategies. Here, we explore the association of chemokine expression with effector T-cell infiltration in PDAC. EXPERIMENTAL DESIGN: Discovery cohorts comprised 113 primary resected PDAC and 107 PDAC liver metastases. Validation cohorts comprised 182 PDAC from The Cancer Genome Atlas and 92 PDACs from the Australian International Cancer Genome Consortium. We explored associations between immune cell counts by immunohistochemistry, chemokine expression, and transcriptional hallmarks of antitumor immunity by RNA sequencing (RNA-seq), and mutational burden by whole-genome sequencing. RESULTS: Among all known human chemokines, a coregulated set of four (CCL4, CCL5, CXCL9, and CXCL10) was strongly associated with CD8+ T-cell infiltration (P < 0.001). Expression of this "4-chemokine signature" positively correlated with transcriptional metrics of T-cell activation (ZAP70, ITK, and IL2RB), cytolytic activity (GZMA and PRF1), and immunosuppression (PDL1, PD1, CTLA4, TIM3, TIGIT, LAG3, FASLG, and IDO1). Furthermore, the 4-chemokine signature marked tumors with increased T-cell activation scores (MHC I presentation, T-cell/APC costimulation) and elevated expression of innate immune sensing pathways involved in T-cell priming (STING and NLRP3 inflammasome pathways, BATF3-driven dendritic cells). Importantly, expression of this 4-chemokine signature was consistently indicative of a T-cell-inflamed phenotype across primary PDAC and PDAC liver metastases. CONCLUSIONS: A conserved 4-chemokine signature marks resectable and metastatic PDAC tumors with an active antitumor phenotype. This could have implications for the appropriate selection of PDAC patients in immunotherapy trials.
Assuntos
Biomarcadores Tumorais/genética , Linfócitos T CD8-Positivos/imunologia , Quimiocina CCL4/genética , Quimiocina CCL5/genética , Quimiocina CXCL10/genética , Quimiocina CXCL9/genética , Neoplasias Hepáticas/secundário , Neoplasias Pancreáticas/patologia , Biomarcadores Tumorais/imunologia , Quimiocina CCL4/imunologia , Quimiocina CCL5/imunologia , Quimiocina CXCL10/imunologia , Quimiocina CXCL9/imunologia , Estudos de Coortes , Biologia Computacional/métodos , Bases de Dados Genéticas/estatística & dados numéricos , Humanos , Proteínas de Checkpoint Imunológico/genética , Imunoterapia/métodos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , RNA-Seq/métodosRESUMO
We integrated clinical, genomic, and transcriptomic data from 224 primaries and 95 metastases from 289 patients to characterize progression of pancreatic ductal adenocarcinoma (PDAC). Driver gene alterations and mutational and expression-based signatures were preserved, with truncations, inversions, and translocations most conserved. Cell cycle progression (CCP) increased with sequential inactivation of tumor suppressors, yet remained higher in metastases, perhaps driven by cell cycle regulatory gene variants. Half of the cases were hypoxic by expression markers, overlapping with molecular subtypes. Paired tumor heterogeneity showed cancer cell migration by Halstedian progression. Multiple PDACs arising synchronously and metachronously in the same pancreas were actually intra-parenchymal metastases, not independent primary tumors. Established clinical co-variates dominated survival analyses, although CCP and hypoxia may inform clinical practice.
