ICRAFT platform identifies new targets for cancer immunotherapy

Professor Zeng Zexian's team from the Center for Quantitative Biology at the Peking University Academy for Advanced Interdisciplinary Studies, in collaboration with the Peking University-Tsinghua University Joint Center for Life Sciences, has developed ICRAFT, an innovative computational platform for identifying cancer immunotherapy targets. Their study has been published in Immunity, an immunology research journal.

Why it matters:
·There is an urgent need for precision immunotherapy strategies that simultaneously target both tumor cells and immune cells to enhance treatment efficacy.
·Identifying genes with dual functions in both cancer and immune cells opens new possibilities for overcoming tumor resistance and improving patient survival.

ICRAFT: A new approach to immunotherapy target discovery
·The research team developed ICRAFT, a CRISPR-based tumor immunotherapy target identification platform.
·ICRAFT integrates:
(i)558 CRISPR screening datasets
(ii)2 million single-cell RNA sequencing datasets
(iii)943 RNA-Seq datasets from clinical immunotherapy samples

By analyzing this large-scale data, ICRAFT systematically identifies genes that regulate both tumor behavior and immune responses, addressing a major gap in immunotherapy research.

Key findings: The dual role of TNFAIP3 (A20)
ICRAFT pinpointed TNFAIP3 (A20) as a crucial gene with dual immunoregulatory effects:
·In tumor cells:
(i)Loss of TNFAIP3 activates TNF-induced apoptosis, upregulates NF-κB signaling, and enhances chemokine expression, promoting T cell infiltration.
(ii)This makes tumor cells more vulnerable to immune destruction.
·In CD8+ T cells:
(i)TNFAIP3 inactivation enhances T cell cytotoxicity, improving their ability to attack and eliminate tumors in the microenvironment.
Additionally, PTPN2 and SOCS1 were identified as genes with similar dual functions, making them potential targets for combination immunotherapy.

Future implications
·ICRAFT is an open-source platform, allowing scientists worldwide to explore new immunotherapy targets, accelerating cancer research.
·The study paves the way for combination therapies that enhance both immune responses and tumor susceptibility.
·By integrating multi-source CRISPR and RNA-Seq data, ICRAFT provides a powerful tool for discovering novel immunotherapy targets, potentially transforming personalized cancer treatment.