Abstract
Somatic gene mutations play a critical role in immune evasion by tumors. However, there is limited information on genes that confer immunotherapy resistance in melanoma. To answer this question, we established a whole-genome knockout B16/ovalbumin cell line by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease technology, and determined by in vivo adoptive OT-I T-cell transfer and an in vitro OT-I T-cell-killing assay that Janus kinase (JAK)1 deficiency mediates T-cell resistance via a two-step mechanism. Loss of JAK1 reduced JAK-Signal transducer and activator of transcription signaling in tumor cells—resulting in tumor resistance to the T-cell effector molecule interferon—and suppressed T-cell activation by impairing antigen presentation. These findings provide a novel method for exploring immunotherapy resistance in cancer and identify JAK1 as potential therapeutic target for melanoma treatment.
Highlights
Melanoma is a common malignant form of skin cancer; once metastasis has occurred, the prognosis is unfavorable
Irradiated B16F10 and MC38 cell lines were used to vaccinate B6 mice three times to stimulate the production of B16F10 or MC38 specific T-cells; sensitivity to T-cells specific to B16F10-sgRNAJAK1 or MC38-sgRNAJAK1 was confirmed (Figures 1D,E). These results suggest that JAK1 loss or mutation contributes to tumor resistance to immunotherapies
Our results demonstrate that: 1) loss of JAK1 induces T-cell resistance in tumor cells in vitro and in vivo; 2) both type I and II IFN pathways are impaired in the absence of Janus kinase (JAK); 3) JAK1deficient tumor cells are resistant to type I and II IFN-induced apoptosis; 4) T-cell activation is compromised in tumor cells lacking JAK1; and 5) exogenous type I IFN can induce regression of JAK1-deficient tumors by activating host non-tumor immune cells (Figure 7)
Summary
Melanoma is a common malignant form of skin cancer; once metastasis has occurred, the prognosis is unfavorable. Immune-based therapies for metastatic melanoma involving cytokines, adoptive T-cell transfer, and checkpoint blockade have achieved some success [1,2,3,4], delayed relapse often occurs after initial tumor arrest or regression even with continuous therapy. About 25% patients with melanoma who received Programmed cell death protein (PD)-1 blockade therapy and were initially responsive but developed resistance after about 21 months [5]. Gene mutations are detected in most cancers including melanoma [11], which has a high mutation load [12]—for instance, mutations in the mitogen-activated protein kinase, phosphatidylinositol 3-kinase/AKT, and HIPPO signaling pathways were shown to mediate immune resistance [13,14,15,16]. Most of the above studies screened components of a single pathway to identify gene mutations conferring immune resistance; as such, there are likely many additional mutations that remain to be identified
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