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Anti-Jagged Immunotherapy Inhibits Mdscs and Overcomes Tumor-Induced Tolerance Rosa A

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Anti-Jagged Immunotherapy Inhibits Mdscs and Overcomes Tumor-Induced Tolerance Rosa A Published OnlineFirst September 13, 2017; DOI: 10.1158/0008-5472.CAN-17-0357 Cancer Microenvironment and Immunology Research Anti-Jagged Immunotherapy Inhibits MDSCs and Overcomes Tumor-Induced Tolerance Rosa A. Sierra1, Jimena Trillo-Tinoco1, Eslam Mohamed1, Lolie Yu2, Bhagelu R. Achyut3, Ali Arbab3, Jennifer W. Bradford4, Barbara A. Osborne5, Lucio Miele2, and Paulo C. Rodriguez1 Abstract Myeloid-derived suppressor cells (MDSC) are a major obstacle and enhanced the efficacy of T-cell–based immunotherapy. to promising forms of cancer immunotherapy, but tools to Depletion of MDSC-like cells restored tumor growth in mice broadly limit their immunoregulatory effects remain lacking. In treated with anti-Jagged, whereas coinjection of MDSC-like cells this study, we assessed the therapeutic effect of the humanized from anti–Jagged-treated mice with cancer cells delayed tumor anti–Jagged1/2-blocking antibody CTX014 on MDSC-mediated growth. Jagged1/2 was induced in MDSCs by tumor-derived T-cell suppression in tumor-bearing mice. CTX014 decreased factors via NFkB-p65 signaling, and conditional deletion of tumor growth, affected the accumulation and tolerogenic activity NFkB-p65 blocked MDSC function. Collectively, our results offer of MDSCs in tumors, and inhibited the expression of immuno- a preclinical proof of concept for the use of anti-Jagged1/2 to suppressive factors arginase I and iNOS. Consequently, anti- reprogram MDSC-mediated T-cell suppression in tumors, with Jagged therapy overcame tumor-induced T-cell tolerance, implications to broadly improve the efficacy of cancer therapy. þ increased the infiltration of reactive CD8 T cells into tumors, Cancer Res; 77(20); 5628–38. Ó2017 AACR. Introduction are needed. Numerous mAb-based therapies have shown promising efficacy as cancer therapeutics through the direct The coordinated activity of the innate and adaptive arms of targeting of tumor antigens or tolerogenic molecules on the immune system is essential to protect individuals against immune cells (5, 6). Although several mAb-based approaches cancer. However, established tumors create a highly tolerogenic have been developed to directly target exhausted or immuno- microenvironment that blocks the development of protective suppressed T cells in cancer patients, there are limited mAb- immunity (1). Myeloid-derived suppressor cells (MDSC) are based therapies that could effectively inhibit MDSCs (7). primary components of the immunosuppressive tumor milieu The Notch family of receptors regulates a highly conserved and are emerging as a major obstacle in the successful devel- pathway that controls the development, differentiation, survival, opment of promising cancer treatments (2). Therapeutic inhi- and function of many cell types, including immune cells (8). bition of the immunosuppressive effects induced by MDSCs in Mammals have four Notch receptors (Notch1 through 4) that are cancer patients treated with chemotherapy, radiotherapy, or bound by five ligands of the Jagged (Jagged1 and Jagged2) and the immunotherapy regimens is thought to be a highly promising Delta-like (DLL1, DLL3, and DLL4) families (9). Binding of Notch strategy with potentially significant clinical impact. However, receptors to the Jagged or DLL membrane ligands induces a two- current approaches to clinically inhibit MDSCs are limited to step proteolytic activation, leading to the intracellular release and multityrosine kinase inhibitors or myelosuppressive agents nuclear translocation of the Notch intracellular active domain that are only partially effective and cause rebounds in MDSC (NICD). Once there, NICD binds to the recombination signal- numbers as the bone marrow recovers (3, 4). Therefore, binding protein-Jk (RBP-Jk) and recruits a mastermind-like new therapeutic strategies to block MDSCs in cancer patients (MAML1-3) coactivator, promoting the transcription of multiple genes (10). In addition, NICD triggers a number of noncanonical þ responses (11, 12). Binding of the Notch receptors on CD8 T 1H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. 2Louisiana cells to DLL ligands on antigen-presenting cells induces antitumor State University Health Sciences Center, New Orleans, Louisiana. 3Georgia cytotoxic responses (13–15), whereas binding of Notch to Jagged Cancer Center, Augusta University, Augusta, Georgia. 4Department of Biological members resulted in suppressive signals (16). The mechanism for 5 Sciences, Augusta University, Augusta, Georgia. Department of Veterinary and this opposite effect remains unclear with possible explanations, Animal Sciences, University of Massachusetts, Amherst, Massachusetts. including different kinetics of Notch activation or selectivity of Note: Supplementary data for this article are available at Cancer Research DLL and Jagged ligands for Notch receptors. Although the effects Online (http://cancerres.aacrjournals.org/). of Notch signaling in innate and adaptive immune responses are Corresponding Author: PauloC.Rodriguez,H.LeeMoffitt Cancer Center the focus of active research, the mechanisms leading to the and Research Institute, 12902 Magnolia Drive MRC-2067E, Tampa, FL, 33612. expression of Jagged molecules in tumors and the potential effect fi Phone: 813-745-1457; E-mail: Paulo.Rodriguez@Mof tt.org of their blockade as a cancer therapy remain largely unknown. doi: 10.1158/0008-5472.CAN-17-0357 In this study, we aimed to test the antitumor effects of Ó2017 American Association for Cancer Research. CTX014, a humanized IgG1-blocking antibody that recognizes 5628 Cancer Res; 77(20) October 15, 2017 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst September 13, 2017; DOI: 10.1158/0008-5472.CAN-17-0357 Anti-Jagged Blocks MDSC-Mediated Immunosuppression in Tumors human and mouse Jagged1 and 2. Our results show that anti- system (Bio-Rad). Densitometry of NFkB-p65 normalized to Jagged therapy triggered antitumor T-cell responses through the nuclear p84 was calculated using the Bio-Rad Image-Lab software. induction of potentially immunogenic MDSC-like cells fi (MDSC-LC; ref. 17). Additional ndings demonstrate the role Cell isolation and suppression assays of NFkB-p65 in the upregulation of Jagged1/2 ligands in Tumors digested with DNAse and Liberase (Roche) were used tumor-associated MDSCs. Thus, results identify a promising to isolate different cellular populations by flow cytometry. 3LL þ therapeutic tool to potentially block MDSCs in tumors, thereby cancer cells were recovered by sorting the CD45neg CD49f cells, addressing a major obstacle in the development of successful whereas tumor-infiltrating myeloid cells were isolated based on þ þ therapies against cancer. the expression of CD45 CD11b . For functional assays, MDSCs from tumors or spleens of tumor-bearing mice or immature Material and Methods myeloid cells (iMC) from spleens of mice without tumors were harvested using magnetic beads, as described previously (18, 20). Cell lines and treatment of mice Purity for each population ranged from 90% to 99%, as detected 3LL Lewis lung carcinoma, MCA-38 colon carcinoma, EL-4 by flow cytometry. Isolated MDSCs were cocultured for 72 hours thymoma, B16-F10 melanoma, and ovalbumin-expressing EL-4 with anti–CD3/CD28-activated T cells labeled with carboxyfluor- (EG-7) cells (ATCC) were injected s.c. into mice, as described escein succinimidyl ester (CFSE) and T-cell proliferation or IFNg previously (18). Tumor cell lines were authenticated on May 2016 expression monitored by flow cytometry (14). Splenic MDSCs and validated to be mycoplasma-free using an ATCC detection kit were cultured for 48 hours with GM-CSF (20 ng/mL) and 30% in June 2016. All experiments were conducted with cells within six 3LL-tumor explants (TES; ref. 21) in the presence of anti-Jagged passages. C57BL/6 mice (6- to 8-week-old female) were pur- antibody (2 mg/mL). chased from Harlan-Envigo. OT-1 and recombination activating gene 1 null (Rag) mice were obtained from The Jackson Labora- flox/flox Adoptive cellular therapy tories. Previously reported NFkB-p65 mice (19) were þ þ crossed with Lysozyme Cre (LysM-Cre) mice. Tumor-bearing For adoptive T-cell transfer (ACT) therapy, CD45.2 mice were mice were treated i.p. with nontoxic concentrations of the anti- injected s.c. with EG-7 cells and started receiving the anti-Jagged or Jagged antibody (CTX-014, Cytomx, 5 mg/kg, every 3 days) or control treatments 6 days after tumor injection. One day later, Â 6 þ þ isotype IgG control (BioXcell, 5 mg/kg) starting on day 6 post- mice received ACT with 1 10 negatively sorted CD45.1 CD8 þ tumor injection and throughout the experiment. To deplete CD8 OT-1 cells that were preactivated for 48 hours with SIINFEKL (14). Ten days later, spleens and tumors were tested for the presence of T cells or MDSC-LC, 3LL-bearing mice were pretreated 1 day neg þ þ before the anti-Jagged injection with 400 mg anti-CD8 (clone the transferred CD45.2 CD45.1 CD8 OT-1 cells and for the 53.6.72; BioXcell) or 250 mg anti–Gr-1 (clone RB6-8C5; BioXcell), expression of IFNg. For Elispot assays, spleens were collected 10 respectively. Maintenance i.p. doses of depleting antibodies were days after OT-1 transfer and activated with 2 mg/mL SIINFEKL for given every 3rd day until tumor endpoint. In MDSC coinjection 24 hours before measuring IFNg production. studies, 1 Â 106 tumor MDSCs from 3LL-bearing mice treated with anti-Jagged or isotype control were coinjected s.c. with 1 Â Hematoxylin & eosin staining and
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