Piperine Inhibits the Immune Checkpoint CD47 to Enhance Immunity Against Pancreatic Cancer.

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Pancreatic cancer is a deadly digestive tract malignancy with poor prognosis.
• Current treatments are limited, highlighting the need for novel therapeutic strategies like immunotherapy.
• Piperine shows potential for inhibiting pancreatic cancer, but its in vivo effects on tumor immunity are unclear.

Purpose of the Study:

• To investigate the effects and mechanisms of piperine on pancreatic cancer progression and anti-tumor immunity in vivo.
• To elucidate piperine's role in modulating the tumor immune microenvironment and its interaction with immune cells.
• To determine if piperine can serve as a novel agent for pancreatic cancer immunotherapy.

Main Methods:

• In vitro studies assessed piperine's effects on pancreatic cancer cell proliferation, migration, and apoptosis.
• In vivo studies utilized mouse models (subcutaneous and orthotopic) to evaluate piperine's impact on tumor growth, metastasis, and immune microenvironment.
• Network pharmacology, RNA-seq, immunohistochemistry, qRT-PCR, Western blot, and flow cytometry were employed to analyze molecular targets and immune cell changes, focusing on CD47.

Main Results:

• Piperine inhibited pancreatic cancer cell proliferation and migration while inducing apoptosis in vitro.
• In vivo, piperine suppressed tumor growth and metastasis in mouse models.
• Piperine increased M1-type macrophages and CD8+ T cells, reduced CD47 expression, enhanced macrophage phagocytosis, and promoted CD8+ T cell activation.

Conclusions:

• Piperine demonstrates significant anti-tumor effects in pancreatic cancer by enhancing anti-tumor immunity.
• Piperine functions by blocking the CD47 immune checkpoint, thereby improving macrophage phagocytosis and CD8+ T cell activation.
• Piperine represents a promising novel therapeutic agent for pancreatic cancer immunotherapy.