Phospholipid Externalization Blockade as an Antitumor Immunotherapy.

Area of Science:

• Immunology
• Cell Biology
• Cancer Research

Background:

• Phospholipid asymmetry, with phosphatidylserine (PS) on the inner plasma membrane leaflet, is crucial in eukaryotic cells.
• In the tumor microenvironment (TME), PS exposure on the outer leaflet from various sources, including apoptotic cells via Xkr8, promotes immune suppression.
• Exposed PS binds to receptors on phagocytes, like macrophages and dendritic cells (DCs), inducing efferocytosis and anti-inflammatory responses.

Purpose of the Study:

• To investigate the role of PS externalization in tumor immune suppression.
• To compare the anti-tumor immune responses in models with constitutive PS exposure (PS^out) versus retained inner leaflet PS (PSⁱⁿ).

Main Methods:

• Development of PS^out tumor models by deleting the PS flippase CDC50A.
• Development of PSⁱⁿ tumor models by knocking out the PS scamblase Xkr8.
• Analysis of anti-tumor immune responses, including macrophage polarization, T cell infiltration, and NK cell cytotoxicity, in these models.

Main Results:

• PS^out tumors showed enhanced growth, M2-polarized tumor-associated macrophages (TAMs), and reduced T cell infiltration, mediated by the PS receptor TIM-3 on TAMs.
• PSⁱⁿ tumors demonstrated suppressed growth, M1-polarized TAMs, reduced IL-10, and enhanced NK cell activity.
• Blocking PS externalization via Xkr8 inhibition showed potential for anti-tumor immunotherapy.

Conclusions:

• A novel engineered protein,
• PS all-block
• neutralizes PS from all sources without triggering immune suppression.
• The "PS all-block" strategy proved more effective than Xkr8 inhibition for anti-tumor immunotherapy by targeting all PS sources.