Identification of essential genes for cancer immunotherapy

By Shashank J. Patel, Neville E. Sanjana, Rigel J. Kishton, A. Eidizadeh, S. Vodnala, Maggie Cam, J. Gartner, Li Jia, S. Steinberg, Tori N. Yamamoto and 14 more. Nature, 2017

770 citations recorded by the source corpus.

Somatic gene mutations can alter the vulnerability of cancer cells to T-cell-based immunotherapies. Here we perturbed genes in human melanoma cells to mimic loss-of-function mutations involved in resistance to these therapies, by using a genome-scale CRISPR–Cas9 library that consisted of around 123,000 single-guide RNAs, and profiled genes whose loss in tumour cells impaired the effector function of CD8+ T cells. The genes that were most enriched in the screen have key roles in antigen presentation and interferon-γ signalling, and correlate with cytolytic activity in patient tumours from The Cancer Genome Atlas. Among the genes validated using different cancer cell lines and antigens, we identified multiple loss-of-function mutations in APLNR, encoding the apelin receptor, in patient tumours that were refractory to immunotherapy. We show that APLNR interacts with JAK1, modulating interferon-γ responses in tumours, and that its functional loss reduces the efficacy of adoptive cell transfer and checkpoint blockade immunotherapies in mouse models. Our results link the loss of essential genes for the effector function of CD8+ T cells with the resistance or non-responsiveness of cancer to immunotherapies.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/d5e9f9b1530986c22f0b18103a74cbdee90a6dce

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Citations in the corpus

A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade (2018, positive): “cell killing (top 10 and top 50) in a genome-scale co-culture screen (Patel et al., 2017); (5) immune-related signatures that were identified based on the analysis of multiple pembrolizumab clinical datasets, and were shown to predict the response to pembrolizumab in an independent cohort (Ayers et ”
Roles of the immune system in cancer: from tumor initiation to metastatic progression (2018, background): “Notably, specific Treg depletion results in tumor cell death and increased production of IFN-γ (Bos et al. 2013; Joshi et al. 2015).”
T Cell Dysfunction in Cancer (2018, background): “Cancer immunotherapy-induced resistance can in some patients be explained by tumorintrinsic alterations, such as defects in the antigen-presentation machinery or inactivation of the IFNg signaling pathway (Patel et al., 2017; Restifo et al., 1996; Zaretsky et al., 2016).”
Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion (2018, background): “Multiple lossof-function mutations in APLNR were identified in patient tumors refractory to immunotherapy (242).”
Genomic features of response to combination immunotherapy in patients with advanced non-small cell lung cancer (2018, background): “, 2016) and pre-clinical reports usingCRISPR/Cas9 screening (Burr et al., 2017;Manguso et al., 2017; Patel et al., 2017) have begun to elucidate genes in both tumors and T cells that are critical to response or resistance to immunotherapy.”
Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation (2021, background): “Mutations in this receptor are found in melanoma patients that are resistant to checkpoint blockade and similarly such resistance is conferred upon knock out of this receptor from mouse melanoma cells (142).”