Natural killer cells and immune-checkpoint inhibitor therapy: Current knowledge and new challenges

Area of Science:

• Immunology
• Cancer Biology
• Pharmacology

Background:

• Immune checkpoints (ICs) regulate immune responses and are crucial in anti-cancer therapy.
• Classical ICs like CTLA4 and PD1 are well-established targets, but ICs on natural killer (NK) cells are emerging targets.
• NK cell receptors such as KIRs and NGK2A are identified as typical NK cell checkpoint members.

Purpose of the Study:

• To review and discuss the potential of dual-checkpoint inhibition targeting both classical and NK cell-specific ICs.
• To explore the role of NK cell ICs in immune cell function and anti-tumor responses.
• To identify novel targets for combined immunotherapy and address potential concerns.

Main Methods:

• Literature review and analysis of existing research on immune checkpoints.
• Identification and definition of classical and non-classical ICs expressed on T and NK cells.
• Discussion of the implications of NK ICs in cancer immunotherapy.

Main Results:

• Several NK cell receptors, including KIRs and NGK2A, function as ICs.
• Dual-checkpoint inhibition targeting both T and NK cell ICs presents a promising synergistic therapeutic strategy.
• NK ICs play a role in NK cell survival, chronic stimulation, and functional exhaustion, impacting anti-tumor immunity.

Conclusions:

• NK cell ICs represent novel targets for developing effective combined immunotherapies.
• Dual-checkpoint inhibition strategies hold significant potential for enhancing anti-cancer treatment efficacy.
• Further research is needed to address concerns and explore the impact of epigenetic drugs in this context.