Extracellular pH modulating injectable gel for enhancing immune checkpoint inhibitor therapy

Area of Science:

• Oncology
• Immunology
• Biomaterials

Background:

• Increased T cell infiltration in tumors correlates with better patient outcomes across various cancer types.
• Tumor acidity (extracellular pH) is a key factor in the tumor microenvironment (TME) that drives immune evasion and tumor progression.
• Modulating the TME's acidity presents a promising strategy for cancer immunotherapy.

Purpose of the Study:

• To investigate the potential of a novel pH-modulating injectable gel (pH$_{e}$-MIG) as a therapeutic agent to alleviate tumor acidity.
• To evaluate the effects of pH$_{e}$-MIG on the tumor immune microenvironment and its combination with immune checkpoint inhibitors (ICIs).
• To elucidate the mechanisms by which extracellular acidity influences T cell function and immune checkpoint pathways.

Main Methods:

• Development and application of Pluronic F-127 based pH$_{e}$-MIG for localized NaHCO$_{3}$ release.
• Intratumoral administration of pH$_{e}$-MIG in a mouse tumor model.
• Assessment of immune cell populations (e.g., CD8+ T cells, suppressive cells) and T cell function within the TME.
• Combination therapy studies involving pH$_{e}$-MIG with anti-PD-1 and anti-TIGIT antibodies.
• Mechanistic studies analyzing co-inhibitory receptor expression, mTOR signaling, and TIGIT/CD155 pathway engagement in T cells.

Main Results:

• Intratumoral pH$_{e}$-MIG treatment reduced suppressive immune cells and increased tumor-infiltrating CD8+ T cells, creating an immune-favorable TME.
• Combination therapy of pH$_{e}$-MIG with anti-PD-1 and anti-TIGIT antibodies resulted in enhanced intratumoral T cell function and significant tumor clearance.
• Extracellular acidity was found to upregulate co-inhibitory immune checkpoint receptors and inhibit mTOR signaling in memory CD8+ T cells, impairing their effector functions.
• Acidic pH environments were shown to increase the expression and engagement of the TIGIT/CD155 pathway, contributing to immune suppression.

Conclusions:

• pH$_{e}$-MIG effectively modulates the tumor microenvironment by alleviating acidity and promoting anti-tumor immunity.
• Combining pH$_{e}$-MIG with ICIs (anti-PD-1, anti-TIGIT) represents a potent strategy for overcoming immune evasion and achieving tumor eradication.
• Understanding the mechanistic link between tumor acidity, T cell dysfunction, and checkpoint receptor regulation provides a rationale for pH-targeted immunotherapies.