In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Immunotherapy using PD-1 checkpoint blockade shows limited efficacy in many cancer patients.
• Novel therapeutic targets are crucial to enhance anti-cancer immune responses.

Purpose of the Study:

• To identify novel immunotherapy targets by screening genes in vivo.
• To discover genetic modifiers of response to PD-1 checkpoint blockade in cancer.

Main Methods:

• A pooled in vivo CRISPR-Cas9 genetic screen was employed in transplantable mouse tumors.
• 2,368 genes in melanoma cells were tested for their role in synergizing with or causing resistance to immunotherapy.
• Tumor cells were treated with immunotherapy (PD-1 checkpoint blockade).

Main Results:

• The screen identified known immune evasion molecules (PD-L1, CD47) and confirmed interferon-gamma signaling defects cause resistance.
• Tumor sensitization to immunotherapy was achieved by deleting genes in pathways including NF-κB signaling, antigen presentation, and the unfolded protein response.
• Deletion of the protein tyrosine phosphatase PTPN2 in tumor cells significantly enhanced immunotherapy efficacy by boosting interferon-gamma mediated antigen presentation and growth suppression.

Conclusions:

• In vivo genetic screens are effective for discovering novel immunotherapy targets.
• PTPN2 deletion represents a potential strategy to sensitize tumors to PD-1 checkpoint blockade therapy.
• Targeting pathways like NF-κB, antigen presentation, and unfolded protein response may overcome immunotherapy resistance.