Details

Autor(en) / Beteiligte

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

Titel

Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations

Ist Teil von

• Cancer discovery, 2017-02, Vol.7 (2), p.188-201

Ort / Verlag

United States

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• Loss-of-function mutations in JAK1/2 can lead to acquired resistance to anti-programmed 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. 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. Cancer Discov; 7(2); 188-201. ©2016 AACR.See related commentary by Marabelle et al., p. 128This article is highlighted in the In This Issue feature, p. 115.