Identification of Natural Killer Cell Enhancers Through Mimicking of the Tumor Microenvironment

Area of Science:

• Immunology
• Cancer Biology
• Pharmacology

Background:

• The tumor microenvironment (TME) contains immunosuppressive factors like kynurenine, prostaglandin E2, and transforming growth factor β (TGFβ).
• These factors inhibit cytotoxic lymphocytes, such as natural killer (NK) cells, enabling cancer cells to evade immune surveillance.
• Restoring NK cell activity is a promising strategy for cancer immunotherapy.

Purpose of the Study:

• To identify small molecules capable of counteracting TME-induced immunosuppression.
• To discover compounds that restore NK cell-mediated cytotoxicity.
• To investigate the mechanisms by which these small molecules exert their effects.

Main Methods:

• Development of a phenotypic co-culture assay for medium-throughput screening of cancer cells and primary lymphocytes.
• Screening of small molecules to identify those that restore NK cell cytotoxicity.
• Characterization of the mechanisms of action for promising compounds, including assessment of TGFβ type I receptor (TGFβR-1) and cyclooxygenase 1 (COX1) inhibition.

Main Results:

• Identification of various small molecules that restore NK cell-mediated cytotoxicity via diverse mechanisms.
• RepSox, a potent TGFβR-1 inhibitor, demonstrated superior efficacy compared to other TGFβR-1 inhibitors.
• RepSox's enhanced activity was attributed to its dual inhibition of TGFβR-1 and cyclooxygenase 1 (COX1), abrogating the effects of multiple immunosuppressive factors.

Conclusions:

• Small molecules can be identified to overcome TME-mediated immunosuppression and enhance anti-tumor immunity.
• RepSox represents a promising therapeutic candidate due to its dual inhibitory action on TGFβR-1 and COX1.
• Targeting multiple immunosuppressive pathways within the TME may be a more effective strategy for restoring NK cell function in cancer therapy.