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The Crosstalk Between Malignant Cells and Tumor-Promoting Immune Cells Relevant to Immunotherapy in Pancreatic Ductal Adenocarcinoma.

ABSTRACT: Background: Pancreatic ductal adenocarcinoma (PDAC) is dominated by an immunosuppressive microenvironment, which makes immune checkpoint blockade (ICB) often non-responsive. Understanding the mechanisms by which PDAC forms an immunosuppressive microenvironment is important for the development of new effective immunotherapy strategies. Methods: This study comprehensively evaluated the cell-cell communications between malignant cells and immune cells by integrative analyses of single-cell RNA sequencing data and bulk RNA sequencing data of PDAC. A Malignant-Immune cell crosstalk (MIT) score was constructed to predict survival and therapy response in PDAC patients. Immunological characteristics, enriched pathways, and mutations were evaluated in high- and low MIT groups. Results: We found that PDAC had high level of immune cell infiltrations, mainly were tumor-promoting immune cells. Frequent communication between malignant cells and tumor-promoting immune cells were observed. 15 ligand-receptor pairs between malignant cells and tumor-promoting immune cells were identified. We selected genes highly expressed on malignant cells to construct a Malignant-Immune Crosstalk (MIT) score. MIT score was positively correlated with tumor-promoting immune infiltrations. PDAC patients with high MIT score usually had a worse response to immune checkpoint blockade (ICB) immunotherapy. Conclusion: The ligand-receptor pairs identified in this study may provide potential targets for the development of new immunotherapy strategy. MIT score was established to measure tumor-promoting immunocyte infiltration. It can serve as a prognostic indicator for long-term survival of PDAC, and a predictor to ICB immunotherapy response.

SUBMITTER: Liu X

PROVIDER: S-EPMC8787220 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is a highly lethal cancer characterized by complex aberrant genomes. A fundamental goal of current studies is to identify those somatic events arising in the variable landscape of PDA genomes that can be exploited for improved clinical outcomes. METHODS: We used DNA content flow sorting to identify and purify tumor nuclei of PDA samples from 50 patients. The genome of each sorted sample was profiled by oligonucleotide comparative genomic hybridization and targeted resequencing of STAG2. Transposon insertions within STAG2 in a KRAS (G12D)-driven genetically engineered mouse model of PDA were screened by RT-PCR. We then used a tissue microarray to survey STAG2 protein expression levels in 344 human PDA tumor samples and adjacent tissues. Univariate Kaplan Meier analysis and multivariate Cox Regression analysis were used to assess the association of STAG2 expression relative to overall survival and response to adjuvant therapy. Finally, RNAi-based assays with PDA cell lines were used to assess the potential therapeutic consequence of STAG2 expression in response to 18 therapeutic agents. RESULTS: STAG2 is targeted by somatic aberrations in a subset (4%) of human PDAs. Transposon-mediated disruption of STAG2 in a KRAS (G12D) genetically engineered mouse model promotes the development of PDA and its progression to metastatic disease. There was a statistically significant loss of STAG2 protein expression in human tumor tissue (Wilcoxon-Rank test) with complete absence of STAG2 staining observed in 15 (4.3%) patients. In univariate Kaplan Meier analysis nearly complete STAG2 positive staining (>95% of nuclei positive) was associated with a median survival benefit of 6.41 months (P?=?0.031). The survival benefit of adjuvant chemotherapy was only seen in patients with a STAG2 staining of less than 95% (median survival benefit 7.65 months; P?=?0.028). Multivariate Cox Regression analysis showed that STAG2 is an independent prognostic factor for survival in pancreatic cancer patients. Finally, we show that RNAi-mediated knockdown of STAG2 selectively sensitizes human PDA cell lines to platinum-based therapy. CONCLUSIONS: Based on these iterative findings we propose that STAG2 is a clinically significant tumor suppressor in PDA.

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The Crosstalk Between Malignant Cells and Tumor-Promoting Immune Cells Relevant to Immunotherapy in Pancreatic Ductal Adenocarcinoma.

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