TY - JOUR
T1 - Primary resistance to PD-1 blockade mediated by JAK1/2 mutations
AU - Shin, Daniel Sanghoon
AU - Zaretsky, Jesse M.
AU - Escuin-Ordinas, Helena
AU - Garcia-Diaz, Angel
AU - Hu-Lieskovan, Siwen
AU - Kalbasi, Anusha
AU - Grasso, Catherine S.
AU - Hugo, Willy
AU - Sandoval, Salemiz
AU - Torrejon, Davis Y.
AU - Palaskas, Nicolaos
AU - Abril-Rodriguez, Gabriel
AU - Parisi, Giulia
AU - Azhdam, Ariel
AU - Chmielowski, Bartosz
AU - Cherry, Grace
AU - Seja, Elizabeth
AU - Berent-Maoz, Beata
AU - Shintaku, I. Peter
AU - Le, Dung T.
AU - Pardoll, Drew M.
AU - Diaz, Luis A.
AU - Tumeh, Paul C.
AU - Graeber, Thomas G.
AU - Lo, Roger S.
AU - Comin-Anduix, Begoña
AU - Ribas, Antoni
N1 - Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/2
Y1 - 2017/2
N2 - 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.
AB - 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.
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U2 - 10.1158/2159-8290.CD-16-1223
DO - 10.1158/2159-8290.CD-16-1223
M3 - Article
C2 - 27903500
AN - SCOPUS:85011827059
SN - 2159-8274
VL - 7
SP - 188
EP - 201
JO - Cancer discovery
JF - Cancer discovery
IS - 2
ER -