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Inactivation of Fbxw7 Impairs Dsrna Sensing and Confers Resistance to PD-1 Blockade

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Inactivation of Fbxw7 Impairs Dsrna Sensing and Confers Resistance to PD-1 Blockade Published OnlineFirst May 5, 2020; DOI: 10.1158/2159-8290.CD-19-1416 RESEARCH ARTICLE Inactivation of Fbxw7 Impairs dsRNA Sensing and Confers Resistance to PD-1 Blockade Cécile Gstalder1,2, David Liu1,3, Diana Miao1, Bart Lutterbach1,2, Alexander L. DeVine1,2, Chenyu Lin4, Megha Shettigar1,2, Priya Pancholi1,2, Elizabeth I. Buchbinder1, Scott L. Carter5,6, Michael P. Manos1, Vanesa Rojas-Rudilla7, Ryan Brennick1, Evisa Gjini8, Pei-Hsuan Chen8, Ana Lako8, Scott Rodig8,9, Charles H. Yoon10, Gordon J. Freeman1, David A. Barbie1, F. Stephen Hodi1, Wayne Miles4, Eliezer M. Van Allen1, and Rizwan Haq1,2 Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst May 5, 2020; DOI: 10.1158/2159-8290.CD-19-1416 ABSTRACT The molecular mechanisms leading to resistance to PD-1 blockade are largely unknown. Here, we characterize tumor biopsies from a patient with melanoma who displayed heterogeneous responses to anti–PD-1 therapy. We observe that a resistant tumor exhibited a loss-of-function mutation in the tumor suppressor gene FBXW7, whereas a sensitive tumor from the same patient did not. Consistent with a functional role in immunotherapy response, inactivation of Fbxw7 in murine tumor cell lines caused resistance to anti–PD-1 in immunocompetent animals. Loss of Fbxw7 was associated with altered immune microenvironment, decreased tumor-intrinsic expression of the double-stranded RNA (dsRNA) sensors MDA5 and RIG1, and diminished induction of type I IFN and MHC-I expression. In contrast, restoration of dsRNA sensing in Fbxw7-deficient cells was suffi- cient to sensitize them to anti–PD-1. Our results thus establish a new role for the commonly inactivated tumor suppressor FBXW7 in viral sensing and sensitivity to immunotherapy. SIGNIFicancE: Our findings establish a role of the commonly inactivated tumor suppressorFBXW7 as a genomic driver of response to anti–PD-1 therapy. Fbxw7 loss promotes resistance to anti–PD-1 through the downregulation of viral sensing pathways, suggesting that therapeutic reactivation of these pathways could improve clinical responses to checkpoint inhibitors in genomically defined cancer patient populations. INTRODUCTION tumor cells, including activation of β-catenin (10, 11) and loss-of-function mutations in JAK1/2 (5) or in the tumor Immunotherapies, such as those targeting CTLA4 and/or suppressor LKB1/STK11 (12). Nevertheless, these mechanisms PD-1, or their combination, have revolutionized the treat- collectively do not account for the majority of cases of immu- ment of patients with cancer (1). However, a key challenge notherapy resistance. Thus, the identification of additional to optimizing the opportunity provided by these therapies is molecular mechanisms of resistance has the potential to the dramatically varied responses among different patients identify patients who are more likely to benefit from these or even among different tumors in the same patient (2). treatments. Elucidation of resistance pathways could also Prior studies have identified decreased CD8+ T-cell infiltra- enable rational therapeutic approaches that restore tumor tion (3), defects in IFN signaling (4, 5) or antigen presen- immunity in genomically selected patient populations. tation (6), as well as alteration of viral sensing pathways FBXW7 is a commonly mutated tumor suppressor in diverse (7–9) as mechanisms leading to therapeutic resistance. These tumor types. Missense mutations in FBXW7 are observed phenotypes can be altered because of oncogenic events in in about 6% of cancers, including endometrial, colon, cervi- cal, stomach, skin, urothelial, lung, ovarian, testis, breast, pancreatic, renal, liver, prostate, brain, and thyroid cancers 1Department of Medical Oncology, Dana-Farber Cancer Institute, (13–15). Approximately 30% of human cancers also have dele- Harvard Medical School, Boston, Massachusetts. 2Division of Molecular tions of chromosome 4q32, which includes the FBXW7 locus and Cellular Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. 3Division of Population Sciences, Dana- (15). Inactivating mutations or the genomic loss of FBXW7 Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. disrupts the activity of an evolutionarily conserved SCF ubiq- 4Department of Molecular Genetics, The Ohio State University, Colum- uitin ligase complex (13, 16–18), leading to increases in cell bus, Ohio. 5Department of Data Sciences, Dana-Farber Cancer Institute, proliferation and division proteins such as MYC, Cyclin E1, 6 Harvard Medical School, Boston, Massachusetts. Division of Computa- and JUN. tional Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. 7Department of CAMD Pathology, Brigham and Although a role of FBXW7 in tumor immunity has not Women’s Hospital, Harvard Medical School, Boston, Massachusetts. yet been shown, a recent report has described a function 8Center for Immuno-Oncology, Dana-Farber Cancer Institute, Harvard of FBXW7 in antiviral immunity through regulating the Medical School, Boston, Massachusetts. 9Department of Pathology, stability of RIG1 (encoded by DDX58; ref. 19). RIG1 and Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. 10Department of Surgery, Brigham and Women’s Hospital, MDA5 (encoded by IFIH1) are two major viral nucleic Harvard Medical School, Boston, Massachusetts. acid sensors that defend against viral infection and other Note: Supplementary data for this article are available at Cancer Discovery pathogens (20). Upon detection of double-stranded RNA Online (http://cancerdiscovery.aacrjournals.org/). (dsRNA) in tumor cells, RIG1 and MDA5 associate with Corresponding Author: Rizwan Haq, Dana-Farber Cancer Institute, 450 MAVS, leading to the recruitment and autophosphoryla- Brookline Avenue, Boston, MA 02215. Phone: 617-632-6168; Fax: 617- tion of TBK1. TBK1 phosphorylates the transcription fac- 632-6727; E-mail: [email protected] tor IRF3, which triggers the expression of type I IFNs and Cancer Discov 2020;10:1–16 proinflammatory cytokines, such as CXCL10. This pathway doi: 10.1158/2159-8290.CD-19-1416 therefore activates innate immune responses in the tumor ©2020 American Association for Cancer Research. microenvironment (21). SEPTEMBER 2020 CANCER DISCOVERY | OF2 Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst May 5, 2020; DOI: 10.1158/2159-8290.CD-19-1416 RESEARCH ARTICLE Gstalder et al. In this study, we found that a loss-of-function mutation ment and the resistant tumor was an arginine-to-cysteine in FBXW7 was associated with resistance to PD-1 blockade mutation at amino acid 505 (R505C) in the tumor suppres- in a patient with melanoma. Using an immunocompetent, sor gene FBXW7 (Fig. 1B and C; Supplementary Table S2). anti–PD-1–sensitive melanoma mouse model, we found that The R505 mutation, the second most common mutation Fbxw7 deletion or its mutation in tumor cells is sufficient to in FBXW7 observed in cancer (Fig. 1D), is associated with confer resistance to PD-1 blockade. Tumor-intrinsic Fbxw7 the increased expression of FBXW7 substrates and leads deficiency altered the tumor immune microenvironment by to dominant-negative phenotypes, suggesting that immu- decreasing immune cell infiltration and diminished the acti- notherapy resistance could be associated with the loss of vation of viral sensing and IFN signaling pathways in vivo. FBXW7 activity. Fbxw7 was essential for the expression of RIG1 and MDA5, which are both required for Fbxw7-mediated dsRNA sensing. Fbxw7 Is Required for the Antitumor Finally, we have shown that restoration of dsRNA sensing in Activity of PD-1 Blockade Fbxw7-deficient cells increased MHC-I expression and sensi- To test the possibility that FBXW7 inactivation leads to tized Fbxw7-deficient tumors to anti–PD-1. These findings resistance to PD-1 blockade in melanoma, we developed a provide insights into the function of the FBXW7 tumor murine melanoma model lacking Fbxw7. Our model was suppressor gene in tumor immunity and suggest a thera- based on D4M3A, a Braf-mutant, Pten-deleted melanoma peutic strategy to overcome resistance to PD-1 blockade in a murine cell line that is 98% genetically identical to C57BL/6 genotype-selected group of patients. mice (27). D4M3A cells were modifiedex vivo to express Cas9 (hereafter denoted D4C9), facilitating the rapid deletion of RESULTS genes by CRISPR (28). Cells transduced with a control guide RNA (sgRNA) grew similarly in immunocompetent C57BL/6 FBXW7 Loss-of-Function Is Associated with and immunocompromised nude mice (Supplementary Figs. Resistance to Pembrolizumab S2A and S2B and S9H and S9I). Anti–PD-1 treatment of To uncover oncogenic mutations that confer resistance to immunocompetent mice with D4C9-sgCtrl tumors was asso- PD-1 blockade, we identified patients with metastatic mela- ciated with durable tumor control (>100 days), even after only noma who exhibited resistance of a single tumor site despite three drug treatments (Supplementary Fig. S2C). Anti–PD-1 responses in other disease sites. One such patient, a 74-year-old treatment had no impact on the survival of nude mice man with diffusely metastatic melanoma (Fig. 1A), exhibited a (Supplementary Fig. S2D). complete response to pembrolizumab in all lesions within 11 To determine whether Fbxw7 is required for response to months of treatment, except for a
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