Targeting CREB remodels the immune microenvironment to enhance immunotherapy responses in pancreatic cancer

Area of Science:

• Oncology
• Cancer Immunology
• Molecular Biology

Background:

• Pancreatic ductal adenocarcinoma (PDAC) presents significant therapeutic challenges.
• Cyclic adenosine monophosphate response element binding protein 1 (CREB) is implicated in PDAC pathogenesis, particularly through its interaction with oncogenic Kras and chronic inflammation.
• Tumor-associated macrophages (TAMs) play a crucial role in the tumor microenvironment and immune suppression in PDAC.

Purpose of the Study:

• To investigate the role of CREB in PDAC growth and immune suppression.
• To elucidate the molecular mechanisms by which CREB influences TAM polarization and T cell infiltration.
• To evaluate the therapeutic potential of targeting the CREB-LIF signaling axis in PDAC.

Main Methods:

• Utilized a genetically engineered mouse model (KPC) for PDAC.
• Employed selective deletion of CREB in KPC mice (KPCC-/-) to assess its impact on disease progression.
• Conducted unbiased transcriptomic analysis, molecular, genetic, and pharmacological approaches in vitro and in vivo.
• Investigated the role of leukemia inhibitory factor (LIF) in mediating CREB's effects on TAMs.
• Administered a CREB-specific inhibitor (CREBi) to target the CREB-LIF axis.

Main Results:

• CREB activation promotes PDAC growth and TAM-mediated immunosuppression in KPC mice.
• Selective deletion of CREB in KPCC-/- mice attenuated primary tumor burden.
• CREB-mediated transcriptional regulation of LIF was identified as a key mediator of tumor cell-macrophage crosstalk, promoting pro-tumor TAM polarization.
• Cancer cell-derived LIF facilitates an immunosuppressive, pro-tumorigenic microenvironment, reducing effector T cell infiltration.
• Pharmacological inhibition of the CREB-LIF axis significantly suppressed tumor growth and sensitized PDAC to immunotherapy.

Conclusions:

• CREB signaling is a critical driver of PDAC growth and immunosuppression through LIF-mediated macrophage reprogramming.
• Targeting the CREB-LIF axis represents a promising therapeutic strategy for PDAC.
• Combination therapy involving CREB inhibition and immunotherapy holds significant potential for improving patient outcomes in PDAC.