Primary resistance to PD-1 blockade mediated by JAK1/2 mutations

By D. Shin, J. Zaretsky, Helena Escuin-Ordinas, A. García-Díaz, S. Hu-Lieskovan, A. Kalbasi, Catherine S. Grasso, Willy Hugo, Salemiz Sandoval, D. Torrejon and 17 more. Cancer Discovery, 2016

1,167 citations recorded by the source corpus.

Loss of function mutations in JAK1/2 can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned they may also be involved in primary resistance to anti-PD-1 therapy. JAK1/2 inactivating mutations were noted in tumor biopsies of 1 of 23 patients with melanoma and in 1 of 16 patients with mismatch repair deficient colon cancer treated with PD-1 blockade. Both cases had a high mutational load but did not respond to anti-PD-1 therapy. Two out of 48 human melanoma cell lines had JAK1/2 mutations, which led to lack of PD-L1 expression upon interferon gamma exposure mediated by inability to signal through the interferon gamma receptor pathway. JAK1/2 loss-of-function alterations in TCGA confer adverse outcomes in patients. We propose that JAK1/2 loss-of-function mutations are a genetic mechanism of lack of reactive PD-L1 expression and response to interferon gamma, leading to primary resistance to PD-1 blockade therapy.

Subfields: Genetics, Oncology

View Paper: https://www.semanticscholar.org/paper/c407b42e4db989f21a8a5c77a517dc23435c2d3d

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In Genetics

1. Ronglai Shen
2. Nicholas D. Socci
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4. P. Keeling

In Oncology

1. J. Wolchok
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Citations in the corpus

• Mechanisms of resistance to immune checkpoint inhibitors (2018, background): “The frequency of such mutations appears low based on limited studies to date, but more widespread sequencing may identify additional mutations that lead to innate and/or acquired resistance to ICI therapy (Zaretsky et al, 2016; Shin et al, 2017).”
• Molecular Determinants of Response to Anti-Programmed Cell Death (PD)-1 and Anti-Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing. (2018, background): “of acquired resistance mediated through defective interferon gamma signaling.(25,34) Of note, the one patient with two trans mutations in B2M and loss-of-protein”
• Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer (2017, background): “Further underscoring the importance of these pathways for resistance to ICIs, defects in the IFN signaling pathway have also been found in melanomas with primary resistance to ipilimumab and pembrolizumab (23) and B2M mutations were recently found in metastatic colon cancers resistant to pembrolizum”
• Genetics and biology of prostate cancer (2018, background): “…IFNGR2, JAK1/2, and IRF1) have emerged as important regulators of primary, adaptive, and acquired immunoresistance in melanoma (Gaoet al. 2016b;Zaretskyet al. 2016; Shin et al. 2017), justifying parallel investigations focused on the basis of the low response rates of mCRPC to immunotherapy.”
• Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression (2017, positive): “There is a renewed interest in interferon signaling given its key role in regulating PD-1 ligand expression and emerging evidence of its role in primary and acquired resistance to immune checkpoint blockade therapy for cancer (Shin et al., 2017; Gao et al., 2016; Zaretsky et al., 2016).”