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AssigneesThe Broad Institute, Inc., Massachusetts Institute of Technology
InventorsJulia Joung, Feng Zhang
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The present disclosure relates to identifying novel tumor immune evasion targets. A CRISPR activation screen was employed to identify novel checkpoint inhibitor targets, where upon upregulation, conferred tumor resistance to cytotoxic T cells in model cancer cell lines. Using MAGeCK and FDR analyses to identify candidate genes that were enriched in cancer cells, B3GNT2, MCL1, BCL2A1 and JUNB were identified as the most enriched after a pathway analysis of the top 576 genes prioritized by MAGeCK. Currently, these four genes have not been identified or suggested as possible checkpoint inhibitor targets. Provided herein are methods of targeting the expression or activity of B3GNT2, MCL1, BCL2A1 and JUNB using small molecule agents and/or gene editing methods with the aim of enhancing anti-tumor immunity in subjects in need thereof.
A method of enhancing anti-tumor immunity in a subject in need thereof comprising administering to the subject one or more agents that reduce the expression or activity of B3GNT2.
A method of enhancing anti-tumor immunity in a subject in need thereof comprising administering to the subject one or more agents that inhibit poly-N-acetyllactosamine (poly-LacNAc) synthesis in tumor cells or reduces poly-LacNAc on surface N- and O-glycans.
A method of enhancing anti-tumor immunity in a subject in need thereof comprising administering to the subject one or more agents capable of inhibiting the expression or activity of MCL1.
A method of enhancing anti-tumor immunity in a subject in need thereof comprising administering to the subject one or more agents capable of inhibiting the expression or activity of BCL2A1.
A method of enhancing anti-tumor immunity in a subject in need thereof comprising administering to the subject one or more agents capable of inhibiting the expression or activity of JUNB.
A method of enhancing anti-tumor immunity in a subject in need thereof comprising administering to the subject one or more agents capable of inhibiting the expression or activity of one or more targets selected from Table 1 or Table 3.
An engineered T cell that expresses an enzyme capable of cleaving poly-LacNAc on the T cell surface.
A method of monitoring the efficacy of an immunotherapy comprising detecting the expression of one or more genes selected from the group consisting of MCL1, BCL2A1, JUNB and B3GNT2 in a subject treated with an immunotherapy, wherein the subject is a non-responder to the immunotherapy if the one or more genes are upregulated after being treated.
A method of screening for agents capable of decreasing poly-LacNAc on tumor cells comprising:
Dependencies are inferred from the claim text.