Tumor-intrinsic SIRPA promotes sensitivity to checkpoint inhibition immunotherapy in melanoma

Area of Science:

• Immunology
• Oncology
• Genomics

Background:

• Checkpoint inhibition immunotherapy, particularly anti-PD-1 therapy, has transformed cancer treatment but faces challenges due to patient resistance.
• Understanding novel targets within the tumor microenvironment is crucial for improving immunotherapy efficacy.

Purpose of the Study:

• To investigate the role of SIRPA (Signal Regulatory Protein Alpha) in melanoma response to anti-PD-1 immunotherapy.
• To explore the mechanisms underlying SIRPA's function in tumor-intrinsic immunity.

Main Methods:

• Integrative transcriptomic and proteomic analyses on bulk and single-cell levels across multiple melanoma clinical cohorts.
• Co-culture systems with melanoma cells and CD8+ T cells.
• In vivo studies using mouse models with SIRPA-deficient and SIRPA-overexpressing melanoma tumors.

Main Results:

• Tumor-intrinsic SIRPA enhances antitumor immunity, contrasting its known inhibitory role in macrophages.
• Loss of SIRPA expression correlates with melanoma dedifferentiation and predicts poor immunotherapy response.
• SIRPA deficiency in melanoma abrogates T cell-mediated tumor killing and immunotherapy efficacy in vivo.
• SIRPA expression is regulated by its pseudogene, SIRPAP1.

Conclusions:

• SIRPA plays a complex, cell-type-dependent role in the tumor ecosystem, exhibiting antagonistic effects on immunotherapy.
• Targeting tumor-intrinsic SIRPA represents a potential strategy to overcome resistance and enhance immunotherapy response in melanoma.