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Genome-Wide CRISPR Screening Identifies JAK1 Deficiency as a Mechanism of T-Cell Resistance

Ping Han1, Qiang Dai1, Lilv Fan1

  • 1School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.

Frontiers in Immunology
|March 7, 2019
PubMed

Insights

Janus kinase 1 (JAK1) deficiency in tumor cells causes resistance to T-cell immunotherapy by reducing interferon signaling and impairing antigen presentation. This identifies JAK1 as a potential therapeutic target for melanoma treatment.

Area of Science:

  • Immunology
  • Oncology
  • Genetics

Background:

  • Somatic gene mutations are crucial for tumor immune evasion.
  • Melanoma immunotherapy resistance mechanisms require further investigation.

Purpose of the Study:

  • To identify genes conferring immunotherapy resistance in melanoma.
  • To elucidate the mechanism of T-cell resistance mediated by gene deficiency.

Main Methods:

  • Established a whole-genome knockout B16/ovalbumin cell line using CRISPR/Cas9 technology.
  • Utilized in vivo adoptive OT-I T-cell transfer and in vitro T-cell-killing assays.

Main Results:

  • Janus kinase 1 (JAK1) deficiency mediates T-cell resistance through a two-step mechanism.
  • Loss of JAK1 reduced JAK-Signal transducer and activator of transcription signaling, leading to tumor resistance to interferon.
  • Impaired antigen presentation due to JAK1 loss suppressed T-cell activation.

Conclusions:

  • JAK1 deficiency confers immunotherapy resistance in melanoma via reduced interferon signaling and impaired antigen presentation.
  • This study presents a novel method for exploring cancer immunotherapy resistance.
  • JAK1 is identified as a potential therapeutic target for melanoma treatment.
Keywords:
CRISPR/Cas9JAK1 deficiencyT-cell resistanceimmunotherapymelanoma

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