Cancer immunology data engine reveals secreted AOAH as a potential immunotherapy

Area of Science:

• Immunology
• Genomics
• Oncology

Background:

• Secreted proteins mediate intercellular communication and are potential therapeutic targets.
• Studying the ~1,903 human secreted protein genes is challenging with traditional genetic methods.
• Discovering novel cancer therapeutics is a critical unmet need.

Purpose of the Study:

• To develop a comprehensive data engine for studying secreted proteins in cancer.
• To identify novel secreted protein targets that can enhance cancer immunotherapy outcomes.
• To validate the role of specific secreted proteins in modulating anti-tumor immunity.

Main Methods:

• Developed the Cancer Immunology Data Engine (CIDE) integrating 90 omics datasets from 8,575 tumor profiles across 17 solid tumor types.
• Systematically identified genes associated with immunotherapy outcomes using CIDE.
• Prioritized secreted proteins with no known cancer roles and validated their function in mouse models.

Main Results:

• CIDE successfully identified genes linked to immunotherapy response.
• Validated four secreted proteins (AOAH, CR1L, COLQ, ADAMTS7) with regulatory effects on immune checkpoint blockade.
• Acyloxyacyl hydrolase (AOAH) emerged as a top hit, potentiating immunotherapy by enhancing T cell receptor sensitivity and protecting dendritic cells.

Conclusions:

• The Cancer Immunology Data Engine (CIDE) is a valuable resource for discovering secreted protein targets in cancer immunotherapy.
• AOAH enhances anti-tumor immunity and represents a promising therapeutic target for improving immunotherapy efficacy.
• Targeting specific secreted proteins can overcome resistance mechanisms and improve patient outcomes in cancer treatment.