A Four-Chemokine Signature Is Associated with a T-cell–Inflamed Phenotype in Primary and Metastatic Pancreatic Cancer

Abstract

◥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 þ 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.

An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer

“…Furthermore, the expression of phagocytosis checkpoint, SIRPa, was lower in the m6Ascore-high group, which may contribute to immune evasion. A chemokine signature which consists of four chemokines (CCL4, CCL5, CXCL9 and CXCL10) was reported to be associated with CD8+ T cells infiltration in PDAC [32]. The current study also found that m6Ascore-low tumors are characterized with increased profiles of CCL and CXCL chemokine ligands, similar to the "T cell-inflamed" phenotype proposed by Romero and colleagues, which may partially explain the distinct immune infiltration profiles between m6Ascore-low and m6Ascore-high tumors.…”

“…The results above indicate m6Ascore is correlated to tumor immune evasion. We investigated the expression of ligands and receptors in Chemokine Ligand (CCL) and chemokine (C-X-C motif) ligand (CXCL) chemokine family, which has been reported to regulate CD8+ T cells infiltration in PDAC [32], and found that most ligands and receptors in CCL and CXCL family decreased in m6Ascore-high tumors, including CCL4 and CCL5 (Fig. 8a).…”

B3GNT3: A prognostic biomarker associated with immune cell infiltration in pancreatic adenocarcinoma

“…CCL2 is required for tumor-associated macrophages to induce immune evasion (26), to promote cancer cell progression (27) and invasion (28). Furthermore, CCL4 is associated with a T cell-inflamed phenotype in primary and metastatic pancreatic cancer (29). Therefore, B3GNT3, as a potential unfavorable prognostic maker, might contribute to the low infiltration of immune cells and immunostimulators.…”

Impaired tumor immune response in metastatic tumors is a selective pressure for neutral evolution in CRC cases

“…To evaluate the tumor immune response level in clinical tissue samples, we examined CYT [26,27], calculated as the geometric mean of GZMA and PRF1 expression values, since both molecules are tightly co-expressed in TCGA samples [19]. GZMA and PRF1 are dramatically upregulated upon CD8+ T cell activation [28].…”