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Loss of aryl hydrocarbon receptor reduces pancreatic tumor growth by increasing immune cell infiltration
Vinicius Kannen1, Ninni E Olafsen2, Siddhartha Das2
1Department of Pharmacology and Toxicology, University of Toronto, Canada.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease which remains poorly understood. Increasing evidence suggests that the aryl hydrocarbon receptor (AHR) plays a role in the pathogenesis of several cancers; however, its role in PDAC is unclear because AHR exhibits both pro- and anti-tumor activities. Here we evaluated the role of AHR in CR705 and K8484 murine PDAC cells in vitro and CR705 cells in vivo. Loss of Ahr did not affect cell proliferation compared with Cas9 control cells and no differences in tumor development between CR705Cas9 and CR705AhrKO cells were observed in immunocompromised mice. Conversely, tumors from CR705AhrKO cells grew more slowly than tumors from CR705Cas9 cells in immune competent mice. RNA sequencing identified 1279 genes upregulated and 586 genes downregulated in CR705AhrKO tumors compared with CR705Cas9 tumors. Pathway analysis identified immunoregulatory interactions, interferon signaling, and chemokine signaling among the top upregulated pathways. Increased infiltration of CD45+ cells and higher numbers of CD8+ T cells and F4/80+ cells were observed in CR705AhrKO tumors. Ahr deficiency in macrophages (LysMCre) or lymphocytes (RorcCre) did not alter tumor development of CR705Cas9 cells compared with Ahrfl/fl mice. CR705AhrKO tumors in RorcCre mice, but not in LysMCre mice had significantly lower tumor weights normalized to body weights compared with CR705AhrKO tumors in WT mice. These findings show that Ahr loss in CR705 pancreatic cancer cells is sufficient to induce proinflammatory gene responses that contribute to increased immune cell infiltration and reduced tumor growth.
Insights
Loss of the aryl hydrocarbon receptor (AHR) in pancreatic cancer cells suppressed tumor growth in immune-competent mice by promoting an anti-tumor immune response. This highlights AHR as a potential therapeutic target in pancreatic ductal adenocarcinoma (PDAC).
Area of Science:
- Oncology
- Cancer Biology
- Immunology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with complex underlying mechanisms.
- The aryl hydrocarbon receptor (AHR) has demonstrated dual roles in cancer, acting as both a promoter and suppressor.
- The specific function of AHR in PDAC pathogenesis remains incompletely understood.
Purpose of the Study:
- To investigate the role of AHR in pancreatic ductal adenocarcinoma (PDAC) using in vitro and in vivo models.
- To determine whether AHR expression influences tumor growth and immune cell infiltration in PDAC.
- To elucidate the molecular pathways affected by AHR loss in PDAC cells.
Main Methods:
- Utilized CR705 and K8484 murine PDAC cell lines with and without AHR (Ahr) gene knockout (KO).
- Assessed tumor development in both immunocompromised and immune-competent mouse models.
- Performed RNA sequencing and pathway analysis on tumor tissues to identify molecular changes.
- Investigated the impact of cell-specific Ahr deficiency in macrophages and lymphocytes.
Main Results:
- Ahr loss did not affect PDAC cell proliferation in vitro or tumor growth in immunocompromised mice.
- Conversely, Ahr-deficient PDAC tumors exhibited slower growth in immune-competent mice.
- RNA sequencing revealed significant alterations in immune-related gene expression, including interferon and chemokine signaling pathways.
- Ahr-deficient tumors showed increased infiltration of immune cells, such as CD8+ T cells and F4/80+ macrophages.
- Tumor growth reduction in Ahr-deficient cells was dependent on lymphocytes, not macrophages.
Conclusions:
- Loss of AHR in PDAC cells can promote an anti-tumor immune response, leading to reduced tumor growth.
- AHR deficiency induces pro-inflammatory gene expression and enhances immune cell infiltration into the tumor microenvironment.
- These findings suggest that targeting AHR may represent a viable therapeutic strategy for PDAC by modulating the anti-tumor immune response.
