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IL-12 Abrogates Calcineurin-Dependent Immune Evasion During Leukemia Progression

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IL-12 Abrogates Calcineurin-Dependent Immune Evasion During Leukemia Progression Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/0008-5472.CAN-18-3800 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. IL-12 abrogates calcineurin-dependent immune evasion during leukemia progression Jennifer L. Rabe,1* Lori Gardner,2* Rae Hunter,3 Jairo A. Fonseca,3 Jodi Dougan,3 Christy M. Gearheart,2 Michael S. Leibowitz,2 Cathy Lee-Miller,2 Dmitry Baturin,2 Susan P. Fosmire,2 Susan E. Zelasko,2 Courtney L. Jones,2 Jill E. Slansky,4 Manali Rupji,5 Bhakti Dwivedi,5 Curtis J. Henry,3,5,6 and Christopher C. Porter3,5,6 Affiliations: 1Molecular Biology Program, University of Colorado Denver, Aurora, CO. 2Department of Pediatrics, University of Colorado, Aurora, CO 3Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 4Integrated Department of Immunology, University of Colorado School of Medicine, Aurora, CO 5Winship Cancer Institute, Emory University, Atlanta, GA 6Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, GA JR and LAG contributed equally to this study. Corresponding Author: Christopher C. Porter, MD Emory University School of Medicine 1760 Haygood Drive, E370 Atlanta, GA 30322 Phone: 404-727-4881 Fax: 404-727-4455 [email protected] Running title: Leukemia-cell calcineurin drives immune evasion Conflict of interest statement The authors have declared that no conflicts of interest exist. Abstract: 199 words Main Text: 5797 words (excluding figure legends and references) Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/0008-5472.CAN-18-3800 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Figures: 7 Tables: 0 Supplemental Files: Supplemental Figures (5) Supplemental Table 1. Supplemental Table 2. 2 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/0008-5472.CAN-18-3800 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Exploitation of the immune system has emerged as an important therapeutic strategy for acute lymphoblastic leukemia (ALL). However, the mechanisms of immune evasion during leukemia progression remain poorly understood. We sought to understand the role of calcineurin in ALL and observed that depletion of calcineurin B (CnB) in leukemia cells dramatically prolongs survival in immune-competent but not immune-deficient recipients. Immune-competent recipients were protected from challenge with leukemia if they were first immunized with CnB- deficient leukemia, suggesting robust adaptive immunity. In the bone marrow, recipients of CnB- deficient leukemia harbored expanded T cell populations as compared to controls. Gene expression analyses of leukemia cells extracted from the bone marrow identified Cn-dependent significant changes in the expression of immunoregulatory genes. Increased secretion of IL-12 from CnB-deficient leukemia cells was sufficient to induce T cell activation ex vivo, an effect that was abolished when IL-12 was neutralized. Strikingly, recombinant IL-12 prolonged survival of mice challenged with highly aggressive B-ALL. Moreover, gene expression analyses from children with ALL showed that patients with higher expression of either IL-12A or IL-12B exhibited prolonged survival. These data suggest that leukemia cells are dependent upon calcineurin for immune evasion by restricting the regulation of pro-inflammatory genes, particularly IL-12. Statement of Significance This report implicates calcineurin as an intracellular signaling molecule responsible for immune evasion during leukemia progression and raises the prospect of re-examining IL-12 as a therapeutic in leukemia. 3 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/0008-5472.CAN-18-3800 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction Despite dramatic improvements in survival for children with acute lymphoblastic leukemia (ALL) over the last few decades, there remain groups of patients for whom novel therapeutic strategies are urgently needed (1). Data implicating the graft vs. leukemia effect (2), and more recent clinical advances in cell-based and antibody therapy for B cell leukemias highlight the potent anti-leukemia activity of the immune system that can be exploited as a treatment option (3-6). Hematological malignancies exhibit unique mechanisms of immune evasion that are not shared with solid tumors (7). Although antigen-specific T cells proliferate early in the tumor course in lymphoid and myeloid tumors (8,9), these cells are unable to trigger the effector functions necessary for tumor rejection (9), and in some cases differentiate into regulatory T cells (Tregs) (8). Several mechanisms have been observed that lead to the development of T cell tolerance. In a murine B cell lymphoma model in which the tumor antigen presentation was restricted to the host antigen presenting cells (APCs), T cells were unresponsive to antigen re-stimulation despite showing a phenotype consisting with antigen recognition (9). Furthermore, activation of the host APCs via CD40 (10) or by inducing the production of Type I interferon (11) improved both the levels of active cytotoxic T cells and mouse survival after myeloid leukemia challenge (10,11). In a murine B-ALL model, direct interaction between the tumor and CD4+ T cells led to the differentiation into Tregs, while abrogating this interaction by knocking down MHC-II in the leukemia cells led to an increase of Th1 CD4+ T cells (8) responsible for the promotion of cell- mediated immunity. However, the mechanisms by which pre-leukemia cells are eliminated by the immune system and how they eventually evade the immune surveillance during leukemia progression are incompletely understood. 4 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/0008-5472.CAN-18-3800 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Calcineurin is a serine/threonine phosphatase that plays a critical role in coupling Ca2+ signals to cellular responses (12). In all tissues except testes, its function is dependent upon the regulatory calcineurin B subunit encoded by Ppp3r1 (CnB). Although calcineurin’s function is best defined in T cells, it has also been studied for its role in oncogenesis and drug resistance in leukemia and lymphoma. For example, BCR-ABL1+ leukemia cells become dependent upon calcineurin when exposed to tyrosine kinase inhibition (13,14). In addition, calcineurin and one of its downstream substrates, NFAT, are activated in lymphoma and leukemia suggesting a role in pathogenesis (15,16). Furthermore, calcineurin was demonstrated to be essential in the development and maintenance of NOTCH and ETV6-JAK2 induced T cell ALL (15,16). The authors of the study concluded that calcineurin is required for leukemia stem cell function in T ALL (15). They and others have recently demonstrated a key role for CXCR4, downstream of calcineurin, in leukemia cell homing and engraftment (17). While investigating the role of leukemia-cell calcineurin in resistance to tyrosine kinase inhibition (13,14), we made the striking observation that calcineurin-deficient leukemia cells engraft and progress in immune-competent recipients, but later regress to below the level of detection, resulting in long-term survival. This is in stark contrast to the Cn-expressing leukemia which rapidly and uniformly progresses to fatal disease within 14-21 days. Due to its role in the regulation of immunomodulatory cytokines in B cells and T cells (18,19), we reasoned that calcineurin in leukemia cells might influence the development of leukemia by altering the bone marrow immune microenvironment, thereby evading immune-mediated elimination. Indeed, transplantation of calcineurin-deficient leukemia into immune-compromised recipients eliminated spontaneous remissions, indicating that leukemia-cell calcineurin is critical for immune evasion. Examination of the bone marrow during leukemogenesis revealed differences in immune cell subsets, with recipients of calcineurin-deficient leukemia having more T cells than recipients of the control, calcineurin-expressing leukemia. Analysis of gene expression indicates that 5 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/0008-5472.CAN-18-3800 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. calcineurin-deficient leukemia cells express higher levels of pro-inflammatory genes. Mechanistically, calcineurin-deficient leukemia cells secrete more cytokines and chemokines than the control leukemia, including IL-12, a potent T cell activator. Neutralization of calcineurin- dependent secretion of IL-12 abrogated leukemia-cell T cell activation ex vivo, and treatment of mice with leukemia with recombinant IL-12 significantly prolonged survival. Gene expression analyses
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