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

Daniel Sanghoon Shin, Jesse M. Zaretsky, Helena Escuin-Ordinas, Angel Garcia-Diaz, Siwen Hu-Lieskovan, Anusha Kalbasi, Catherine S. Grasso, Willy Hugo, Salemiz Sandoval, Davis Y. Torrejon, Nicolaos Palaskas, Gabriel Abril-Rodriguez, Giulia Parisi, Ariel Azhdam, Bartosz Chmielowski, Grace Cherry, Elizabeth Seja, Beata Berent-Maoz, I. Peter Shintaku, Dung T. LeDrew M. Pardoll, Luis A. Diaz, Paul C. Tumeh, Thomas G. Graeber, Roger S. Lo, Begoña Comin-Anduix, Antoni Ribas

Research output: Contribution to journalArticle

Abstract

Loss-of-function mutations in JAK1 / 2 can lead to acquired resistance to antiprogrammed death protein 1 (PD-1) therapy. We reasoned that 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 a lack of PD-L1 expression upon interferon gamma exposure mediated by an inability to signal through the interferon gamma receptor pathway. JAK1/2 loss-of-function alterations in The Cancer Genome Atlas 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. SIGNIFICANCE: A key functional result from somatic JAK1/2 mutations in a cancer cell is the inability to respond to interferon gamma by expressing PD-L1 and many other interferon-stimulated genes. These mutations result in a genetic mechanism for the absence of reactive PD-L1 expression, and patients harboring such tumors would be unlikely to respond to PD-1 blockade therapy.

Original languageEnglish (US)
Pages (from-to)188-201
Number of pages14
JournalCancer discovery
Volume7
Issue number2
DOIs
StatePublished - Feb 2017

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ASJC Scopus subject areas

  • Oncology

Cite this

Shin, D. S., Zaretsky, J. M., Escuin-Ordinas, H., Garcia-Diaz, A., Hu-Lieskovan, S., Kalbasi, A., Grasso, C. S., Hugo, W., Sandoval, S., Torrejon, D. Y., Palaskas, N., Abril-Rodriguez, G., Parisi, G., Azhdam, A., Chmielowski, B., Cherry, G., Seja, E., Berent-Maoz, B., Shintaku, I. P., ... Ribas, A. (2017). Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer discovery, 7(2), 188-201. https://doi.org/10.1158/2159-8290.CD-16-1223