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

Cancer Discovery - Tập 7 Số 2 - Trang 188-201 - 2017
Daniel Sanghoon Shin1, Jesse M. Zaretsky1, Helena Escuin-Ordinas1, Ángel García-Díaz1, Siwen Hu‐Lieskovan1, Anusha Kalbasi1, Catherine S. Grasso1, Willy Hugo1, Salemiz Sandoval1, Davis Y. Torrejon1, Nicolaos Palaskas1, Gabriel Abril Rodriguez1, Giulia Parisi1, Ariel M. Azhdam1, Bartosz Chmielowski1,2, Grace Cherry1, Elizabeth Seja1, Beata Berent-Maoz1, I. Peter Shintaku1, Dung T. Le3, Drew M. Pardoll3, Luis A. Díaz3, Paul C. Tumeh1, Thomas G. Graeber1,2, Roger S. Lo1,2, Begoña Comı́n-Anduix1,2, Antoni Ribas1,2
11University of California, Los Angeles (UCLA), Los Angeles, California.
22Jonsson Comprehensive Cancer Center, Los Angeles, California.
33Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.

Tóm tắt

Abstract 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. 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. Cancer Discov; 7(2); 188–201. ©2016 AACR. See related commentary by Marabelle et al., p. 128. This article is highlighted in the In This Issue feature, p. 115

Từ khóa


Tài liệu tham khảo

Herbst, 2014, Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients, Nature, 515, 563, 10.1038/nature14011

Powles, 2014, MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer, Nature, 515, 558, 10.1038/nature13904

Robert, 2015, Nivolumab in previously untreated melanoma without BRAF mutation, N Engl J Med, 372, 320, 10.1056/NEJMoa1412082

Ansell, 2015, PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma, N Engl J Med, 372, 311, 10.1056/NEJMoa1411087

Robert, 2015, Pembrolizumab versus ipilimumab in advanced melanoma, N Engl J Med, 372, 2521, 10.1056/NEJMoa1503093

Le, 2015, PD-1 blockade in tumors with mismatch-repair deficiency, N Engl J Med, 372, 2509, 10.1056/NEJMoa1500596

Garon, 2015, Pembrolizumab for the treatment of non-small-cell lung cancer, N Engl J Med, 372, 2018, 10.1056/NEJMoa1501824

Nghiem, 2016, PD-1 blockade with pembrolizumab in advanced merkel-cell carcinoma, N Engl J Med, 374, 2542, 10.1056/NEJMoa1603702

Pardoll, 2012, The blockade of immune checkpoints in cancer immunotherapy, Nature reviews Cancer, 12, 252, 10.1038/nrc3239

Taube, 2012, Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape, Sci Transl Med, 4, 127ra37, 10.1126/scitranslmed.3003689

Tumeh, 2014, PD-1 blockade induces responses by inhibiting adaptive immune resistance, Nature, 515, 568, 10.1038/nature13954

Ribas, 2015, Adaptive immune resistance: how cancer protects from immune attack, Cancer Discov, 5, 915, 10.1158/2159-8290.CD-15-0563

Bach, 1997, The IFN gamma receptor: a paradigm for cytokine receptor signaling, Annu Rev Immunol, 15, 563, 10.1146/annurev.immunol.15.1.563

Zaretsky, 2016, Mutations associated with acquired resistance to PD-1 blockade in melanoma, N Engl J Med, 375, 819, 10.1056/NEJMoa1604958

Dunn, 2002, Cancer immunoediting: from immunosurveillance to tumor escape, Nat Immunol, 3, 991, 10.1038/ni1102-991

Kaplan, 1998, Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice, Proc Natl Acad Sci U S A, 95, 7556, 10.1073/pnas.95.13.7556

Mazzolini, 2003, Pancreatic cancer escape variants that evade immunogene therapy through loss of sensitivity to IFNgamma-induced apoptosis, Gene Ther, 10, 1067, 10.1038/sj.gt.3301957

Gao, 2016, Loss of IFN-gamma pathway genes in tumor cells as a mechanism of resistance to Anti-CTLA-4 Therapy, Cell, 167, 397, 10.1016/j.cell.2016.08.069

Rizvi, 2015, Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer, Science, 348, 124, 10.1126/science.aaa1348

Hugo, 2016, Genomic and transcriptomic features of response to Anti-PD-1 therapy in metastatic melanoma, Cell, 165, 35, 10.1016/j.cell.2016.02.065

Rosenberg, 2016, Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial, Lancet, 387, 1909, 10.1016/S0140-6736(16)00561-4

Rodig, 1998, Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses, Cell, 93, 373, 10.1016/S0092-8674(00)81166-6

Muller, 1993, The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction, Nature, 366, 129, 10.1038/366129a0

Watling, 1993, Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-gamma signal transduction pathway, Nature, 366, 166, 10.1038/366166a0

Barretina, 2012, The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity, Nature, 483, 603, 10.1038/nature11003

Ren, 2013, JAK1 truncating mutations in gynecologic cancer define new role of cancer-associated protein tyrosine kinase aberrations, Scientific reports, 3, 3042, 10.1038/srep03042

Platanias, 2005, Mechanisms of type-I- and type-II-interferon-mediated signalling, Nat Rev Immunol, 5, 375, 10.1038/nri1604

Fish, 2014, Interferon receptor signaling in malignancy: a network of cellular pathways defining biological outcomes, Mol Cancer Res, 12, 1691, 10.1158/1541-7786.MCR-14-0450

Dunn, 2005, IFN unresponsiveness in LNCaP cells due to the lack of JAK1 gene expression, Cancer Res, 65, 3447, 10.1158/0008-5472.CAN-04-4316

Spranger, 2015, Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity, Nature, 523, 231, 10.1038/nature14404

Sharma, 2015, The future of immune checkpoint therapy, Science, 348, 56, 10.1126/science.aaa8172

Ribas, 2016, Association of pembrolizumab with tumor response and survival among patients with advanced melanoma, JAMA, 315, 1600, 10.1001/jama.2016.4059

Nazarian, 2010, Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation, Nature, 468, 973, 10.1038/nature09626

Atefi, 2014, Effects of MAPK and PI3K Pathways on PD-L1 expression in melanoma, Clin Cancer Res, 20, 3446, 10.1158/1078-0432.CCR-13-2797

Wong, 2014, Antitumor activity of the ERK inhibitor SCH722984 against BRAF mutant, NRAS mutant and wild-type melanoma, Mol Cancer, 13, 194, 10.1186/1476-4598-13-194

Wolchok, 2009, Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria, Clin Cancer Res, 15, 7412, 10.1158/1078-0432.CCR-09-1624

Kotecha, 2010, Web-based analysis and publication of flow cytometry experiments, Current protocols in cytometry/editorial board, 10.1002/0471142956.cy1017s53

Escuin-Ordinas, 2014, COX-2 inhibition prevents the appearance of cutaneous squamous cell carcinomas accelerated by BRAF inhibitors, Mol Oncol, 8, 250, 10.1016/j.molonc.2013.11.005

Shi, 2014, Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy, Cancer Discov, 4, 80, 10.1158/2159-8290.CD-13-0642

Cibulskis, 2013, Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples, Nat Biotechnol, 31, 213, 10.1038/nbt.2514

Koboldt, 2012, VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing, Genome research, 22, 568, 10.1101/gr.129684.111

Ramos, 2015, Oncotator: cancer variant annotation tool, Human mutation, 36, E2423, 10.1002/humu.22771

McGranahan, 2016, Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade, Science, 351, 1463, 10.1126/science.aaf1490

Favero, 2015, Sequenza: allele-specific copy number and mutation profiles from tumor sequencing data, Ann Oncol, 26, 64, 10.1093/annonc/mdu479

Cerami, 2012, The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data, Cancer Discov, 2, 401, 10.1158/2159-8290.CD-12-0095

Gao, 2013, Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal, Sci Signal, 6, pl1, 10.1126/scisignal.2004088

Beroukhim, 2007, Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma, Proc Natl Acad Sci U S A, 104, 20007, 10.1073/pnas.0710052104

Thông tin
Thông tin xuất bản

Cancer Discovery

Tập 7 Số 2

188-201

Thông tin tác giả