Blockade of LIF and PD-L1 Enhances Chemotherapy in Preclinical PDAC Models

Area of Science:

• Oncology
• Immunotherapy
• Cancer Biology

Background:

• Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death, often resistant to immunotherapy due to an immunosuppressive tumor microenvironment (TME).
• Leukemia inhibitory factor (LIF) drives PDAC stemness, epithelial-mesenchymal transition (EMT), and therapy resistance.
• Previous trials indicate anti-LIF therapy is safe but requires combination strategies for improved efficacy.

Purpose of the Study:

• To evaluate the efficacy of combining chemotherapy (gemcitabine/nab-paclitaxel) with dual blockade of LIF and PD-L1 in PDAC models.
• To investigate the impact of this combination therapy on tumor growth, survival, and the antitumor immune response.

Main Methods:

• Utilized orthotopic and spontaneous PDAC models to assess treatment efficacy.
• Employed flow cytometry and single-cell RNA sequencing (scRNA-seq) to analyze immune cell responses.
• Investigated the role of CD4, CD8, and inflammatory monocytes through immune cell depletion studies.

Main Results:

• Sequential chemo/anti-LIF/anti-PD-L1 treatment demonstrated superior antitumor efficacy compared to monotherapy or dual combinations.
• The combination therapy reduced EMT in tumor cells and significantly enhanced CD8 T cell-mediated antitumor immunity.
• Immune cell depletion studies confirmed the critical role of CD8 T cells in mediating treatment effects.
• Combination therapy promoted an antitumor phenotype in macrophages and dendritic cells.

Conclusions:

• The combination of chemotherapy, anti-LIF, and anti-PD-L1 therapy effectively targets PDAC tumor cells and augments the anti-tumor immune response.
• These findings provide strong preclinical support for advancing this triple combination therapy into clinical trials for PDAC treatment.