JAKing up resistance to immunotherapy

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Science Immunology  06 Oct 2017:
Vol. 2, Issue 16, eaaq0015
DOI: 10.1126/sciimmunol.aaq0015


A two-cell type CRISPR screen has identified genes and pathways that mediate resistance to cancer immunotherapy.

Tumors arise from the accumulation of somatic mutations that activate oncogenes or cause the inactivation of tumor suppressor genes, resulting in increased clonal proliferation and in some cases metastatic spreading. Somatic mutations and epigenetic alterations also contribute to the tumors’ ability to evade host immunity. The existing modalities of immune checkpoint blockade typically reawaken somnolent adaptive immune cells that have been rendered nonfunctional by tumor cells or by the tumor microenvironment. Adoptive cell therapies involve the introduction of in vitro activated or engineered immune cells into cancer patients. Immunotherapies are not universally effective, partly because many tumors acquire somatic mutations that limit their susceptibility to immunotherapy.

Patel et al. used a “two-cell type” clustered regularly interspaced short palindromic repeats (CRISPR) assay combining a melanoma cell line expressing the NY-ESO-1 antigen and human primary CD8+ T cells that had been transduced with the T cell receptor α (TCRα) and TCRβ genes encoding a TCR-specific for a human lymphocyte antigen (HLA) class-I restricted NY-ESO-1 peptide. They mutagenized the human melanoma cells using a CRISPR-Cas9 library containing about 123,000 guide RNAs and identified loss-of-function mutations that rendered the tumor resistant to the cocultured tumor-specific cytotoxic T cells. Many of the mutations identified were in genes already known to be linked to antigen presentation or interferon-γ (IFN-γ) signaling. A set of genes that had not previously been connected to the effector functions of T cells was also identified. Multiple loss-of-function mutations were detected in the APLNR gene that encodes the apelin receptor (APLNR). APLNR was found to interact with Janus kinase 1 (JAK1) and to modulate the responses of tumor cells to IFN-γ. To examine the relevance of APLNR in the in vivo setting of immunotherapy, the authors targeted the murine Aplnr gene in a B16 melanoma cells using CRISPR or RNA interference and transferred either the original or modified melanoma cells along with tumor-specific T cells into recipient mice. When Aplnr was mutated or knocked down, tumors were more resistant to immunotherapy.

These studies and future screens of this sort will help identify current barriers to immunotherapy and guide future approaches to overcome them.


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