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Loss of aryl hydrocarbon receptor reduces pancreatic tumor growth by increasing immune cell infiltration

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease which despite large research efforts remains poorly understood. Many studies provide evidence that the aryl hydrocarbon receptor (AHR) plays a critical role in the pathogenesis of several cancers and represents new anti-cancer therapeutic target. The role of AHR in PDAC is, however, unclear since AHR has been reported to exhibit both pro- and anti-tumor activities. In this study we evaluated the role of AHR in murine PDAC cells in vitro and in vivo. Loss of AHR did not affect cell proliferation compared with wildtype (WT). Consistent with these findings, no differences in tumor development between WT and AhrKO cells were observed in immunocompromised mice. However, tumors from AhrKO cells grew more slowly than tumors from WT cells in immune competent mice. RNA sequencing of the tumors resulted in 1009 genes upregulated and 477 genes downregulated in AhrKO tumors compared with WT tumors. Pathway analysis identified immunoregulatory interactions, interferon signaling, interleukin signaling and PD1 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 AhrKO tumors. Analysis of the F4/80+ cell populations revealed a lower percentage of anti-inflammatory (M2) macrophages in AhrKO tumors. Ahr deficiency in macrophages (LysMCre) or lymphocytes (RorcCre) did not alter tumor development of WT cells compared with WT C57BL/6 mice. AhrKO tumors in RorcCre mice, but not in LysMCre mice had significantly lower tumor weights normalized to body weights compared with AhrKO tumors in WT mice. These findings show that tumors derived from AhrKO pancreatic cancer cells exhibit a proinflammatory gene responses that contribute to increased immune cell infiltration and reduced tumor growth. They also suggesting that loss of AHR in lymphocytes together Ahr loss in cancer cells further reduces tumor growth.

ORGANISM(S): Mus musculus

PROVIDER: GSE279893 | GEO | 2025/01/03

REPOSITORIES: GEO

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Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.

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Loss of aryl hydrocarbon receptor reduces pancreatic tumor growth by increasing immune cell infiltration

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