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Melanoma response to anti-PD-L1 immunotherapy requires JAK1 signaling, but not JAK2.

ABSTRACT: Immunotherapies targeting programmed cell death protein 1 (PD-1) or its ligand, programmed cell death ligand 1 (PD-L1), dramatically improve the survival of melanoma patients. However, only ∼40% of treated patients demonstrate a clinical response to single-agent anti-PD-1 therapy. An intact tumor response to type-II interferon (i.e. IFN-γ) correlates with response to anti-PD-1, and patients with de novo or acquired resistance may harbor loss-of-function alterations in the JAK/STAT pathway, which lies downstream of the interferon gamma receptor (IFNGR1/2). In this study, we dissected the specific roles of individual JAK/STAT pathway members on the IFN-γ response, and identified JAK1 as the primary mediator of JAK/STAT signaling associated with IFN-γ-induced expression of antigen-presenting molecules MHC-I and MHC-II, as well as PD-L1 and the cytostatic response to IFN-γ. In contrast to the crucial role of JAK1, JAK2 was largely dispensable in mediating most IFN-γ effects. In a mouse melanoma model, inhibition of JAK1/2 in combination with anti-PD-L1 therapy partially blocked anti-tumor immunologic responses, while selective JAK2 inhibition appeared to augment therapy. Amplification of JAK/STAT signaling in tumor cells through genetic inhibition of the negative regulator PTPN2 potentiated IFN-γ response in vitro and in vivo, and may be a target to enhance immunotherapy efficacy.

SUBMITTER: Luo N

PROVIDER: S-EPMC5975601 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Immunotherapy response score (IRS) integrates tumor mutation burden (TMB) and quantitative expression biomarkers to predict anti-PD-1/PD-L1 [PD-(L)1] monotherapy benefit. Here, we evaluated IRS in additional cohorts. Patients from an observational trial (NCT03061305) treated with anti-PD-(L)1 monotherapy were included and assigned to IRS-High (-H) versus -Low (-L) groups. Associations with real-world progression-free survival (rwPFS) and overall survival (OS) were determined by Cox proportional hazards (CPH) modeling. Those with available PD-L1 IHC treated with anti-PD-(L)1 with or without chemotherapy were separately assessed. Patients treated with PD-(L)1 and/or chemotherapy (five relevant tumor types) were assigned to three IRS groups [IRS-L divided into IRS-Ultra-Low (-UL) and Intermediate-Low (-IL), and similarly assessed]. In the 352 patient anti-PD-(L)1 monotherapy validation cohort (31 tumor types), IRS-H versus IRS-L patients had significantly longer rwPFS and OS. IRS significantly improved CPH associations with rwPFS and OS beyond microsatellite instability (MSI)/TMB alone. In a 189 patient (10 tumor types) PD-L1 IHC comparison cohort, IRS, but not PD-L1 IHC nor TMB, was significantly associated with anti-PD-L1 rwPFS. In a 1,103-patient cohort (from five relevant tumor types), rwPFS did not significantly differ in IRS-UL patients treated with chemotherapy versus chemotherapy plus anti-PD-(L)1, nor in IRS-H patients treated with anti-PD-(L)1 versus anti-PD-(L)1 + chemotherapy. IRS associations were consistent across subgroups, including both Europeans and non-Europeans. These results confirm the utility of IRS utility for predicting pan-solid tumor PD-(L)1 monotherapy benefit beyond available biomarkers and demonstrate utility for informing on anti-PD-(L)1 and/or chemotherapy treatment.SignificanceThis study confirms the utility of the integrative IRS biomarker for predicting anti-PD-L1/PD-1 benefit. IRS significantly improved upon currently available biomarkers, including PD-L1 IHC, TMB, and MSI status. Additional utility for informing on chemotherapy, anti-PD-L1/PD-1, and anti-PD-L1/PD-1 plus chemotherapy treatments decisions is shown.

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Melanoma response to anti-PD-L1 immunotherapy requires JAK1 signaling, but not JAK2.

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