Shaping Tumor Microenvironment by Amplifying the Complement Cascade for Improved Immune Response in Pancreatic Cancer...

Area of Science:

• Immunology
• Oncology
• Biochemistry

Background:

• Natural antibodies against αGal are abundant in humans and crucial for cancer immunotherapy via complement activation.
• Properdin (FP) is the sole known positive regulator of the complement system.
• Enhancing complement activation is a potential strategy to improve cancer immunotherapy efficacy.

Purpose of the Study:

• To investigate the potential of membrane-anchored properdin (mFP) to enhance αGal-mediated complement activation for cancer immunotherapy.
• To assess the impact of mFP expression on pancreatic cancer growth and the tumor microenvironment (TME).
• To develop and evaluate a novel, engineered mFP for improved complement activation.

Main Methods:

• Ectopic expression of mFP on mouse and human pancreatic cancer cells (Panc02).
• Assessment of αGal-mediated complement activation, C3 deposition, and complement-dependent cytotoxicity (CDC) in vitro.
• In vivo studies using an immunized Ggta1 knockout mouse model to evaluate tumor growth and TME changes.
• Development of a reconfigured mFP with an artificial C3 convertase binding site and intracellular oligomerization domain for functional testing in a human whole blood loop model.

Main Results:

• mFP expression on Panc02 cells increased C3 deposition and CDC in the presence of human complement.
• In vivo, mFP expression significantly delayed tumor growth in the Ggta1 knockout mouse model.
• mFP altered the TME, increasing conventional type 1 dendritic cells, reducing pro-tumorigenic monocytes/macrophages, and shifting CD8+ T cells to a progenitor-exhausted state.
• The engineered mFP demonstrated improved target cell killing and phagocytosis in a human whole blood loop model.

Conclusions:

• Amplifying complement activation via mFP can delay tumor growth and beneficially modulate the TME in a pancreatic cancer model.
• The developed membrane-bound, oligomerized FP functional unit effectively elicits robust complement activation.
• This strategy holds promise for enhancing cancer immunotherapy by leveraging the complement system.