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Il-36 Gamma Promotes Anti-Tumor Immunity Through Therapeutic Induction of Tumor-Associated Tertiary Lymphoid Structures

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Il-36 Gamma Promotes Anti-Tumor Immunity Through Therapeutic Induction of Tumor-Associated Tertiary Lymphoid Structures IL-36 GAMMA PROMOTES ANTI-TUMOR IMMUNITY THROUGH THERAPEUTIC INDUCTION OF TUMOR-ASSOCIATED TERTIARY LYMPHOID STRUCTURES by Aliyah Miel Weinstein B.A., Rutgers, the State University of New Jersey, 2012 Submitted to the Graduate Faculty of the School of Medicine in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2018 UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE This dissertation was presented by Aliyah Miel Weinstein It was defended on March 16, 2018 and approved by Lisa H. Butterfield, PhD, Professor, Department of Medicine Binfeng Lu, PhD, Associate Professor, Department of Immunology Adrian E. Morelli, MD, PhD, Associate Professor, Departments of Surgery and Immunology Donna Beer Stolz, PhD, Associate Professor, Department of Cell Biology Dissertation Advisor: Walter J. Storkus, PhD, Professor, Department of Dermatology ii Copyright © by Aliyah Miel Weinstein 2018 iii IL-36 GAMMA PROMOTES ANTI-TUMOR IMMUNITY THROUGH THERAPEUTIC INDUCTION OF TUMOR-ASSOCIATED TERTIARY LYMPHOID STRUCTURES Aliyah Miel Weinstein, PhD University of Pittsburgh, 2018 The last decade has advanced our understanding of the composition of the tumor- immune microenvironment and its role as a potential target for therapeutic intervention. Recently, tertiary lymphoid structures have been observed to develop in the tumor microenvironment and serve as a positive prognostic marker in many types of solid tumors. The major signals that control tertiary lymphoid organogenesis are the same as those that direct the development of secondary lymphoid organs. Tertiary lymphoid structures are classically characterized by high endothelial venules, which serve to recruit T cells, dendritic cells, and B cells to sites of persistent inflammation and locally prime T cells against tumor-derived antigens. Our group has long been interested in understanding whether tertiary lymphoid structures can be therapeutically induced to form within the tumor microenvironment and induce a protective anti-tumor immune response. In previous studies, we characterized dendritic cells engineered to overexpress the Type-1 transactivator Tbet (i.e. DC.Tbet) and showed that they are able to delay tumor progression following intratumoral injection in a murine model of sarcoma. In this work, I show that the effector molecule responsible for the therapeutic efficacy of DC.Tbet is IL-36γ. Dendritic cells engineered to ectopically overexpress IL- 36γ and injected intratumorally into the murine MC38 model of colorectal carcinoma can direct the same magnitude of immune response as DC.Tbet therapy, even in the absence of Tbet expression by the injected cells. IL-36γ drives intratumoral expression of lymphotoxins and chemokines that direct tertiary lymphoid organogenesis, and promotes an intratumoral Type-1 immune response in conjunction with delayed tumor progression. Finally, I evaluated the expression pattern of IL-36γ in human colorectal cancer. I show that within the immune compartment, expression of IL-36γ by M1 macrophages is positively correlated with a high CD4+ central memory T cell infiltrate into those tumors; and that IL-36γ expression on the tumor vasculature is associated with an increased density of B cells within tumor-associated tertiary lymphoid structures. Together, these data support IL-36γ as a novel mediator of anti-tumor immunity and its further investigation as a therapeutic agent to enhance protective Type-1 immune responses in the tumor microenvironment. v TABLE OF CONTENTS PREFACE ..................................................................................................................... xvi ABBREVIATIONS ....................................................................................................... xviii 1.0 INTRODUCTION ....................................................................................................... 1 1.1 IMMUNE RESPONSES IN THE TUMOR MICROENVIRONMENT ....................... 1 1.1.2 Tbet has a multitude of roles in the immune response, including the promotion of Type-1 immunity ................................................................................................... 2 1.1.3 DCs in cancer .................................................................................................. 4 1.1.3.1 Endogenous DCs .................................................................................................................. 4 1.1.3.2 DC-based immunotherapies ................................................................................................. 5 1.1.3.3 Perspectives on DC-based Immunotherapy ......................................................................... 6 1.2 THERAPEUTIC LYMPHOID ORGANOGENESIS IN THE TUMOR MICROENVIROMENT ................................................................................................. 6 1.2.1 Abstract............................................................................................................ 7 1.2.2 Introduction ...................................................................................................... 8 1.2.3 Development of TLS in Chronically-Diseased Tissues .................................... 8 1.2.3.1 TLS: Organizational structure ............................................................................................. 10 1.2.4 TLS in cancer: Clinical Correlates of Disease Progression and Response to Treatment ............................................................................................................... 11 1.2.5 Cues for TLS Development ............................................................................ 17 vi 1.2.5.1 The requirement for lymphotoxin signaling in the evolution of TLS in the TME ................. 18 1.2.5.2 EnLIGHTening Protective Immunity in TLS ........................................................................ 21 1.2.5.3 The Importance of CCR7 Agonists for TLS Evolution in the TME ...................................... 25 1.2.5.4 The Importance of CXCR5 agonists in TLS evolution ........................................................ 29 1.2.6 Therapeutic Manipulation of TLS in Cancer Patients: Establishing a Paradigm for Anti-Tumor Efficacy ........................................................................................... 32 1.2.7 Conclusions and Future Directions for Clinical Translation ............................ 32 1.3 BIOSYNTHESIS AND FUNCTIONAL SIGNIFICANCE OF PERIPHERAL NODE ADDRESSIN IN CANCER-ASSOCIATED TLS ......................................................... 34 1.3.1 Abstract.......................................................................................................... 34 1.3.2 Pathways regulating PNAd expression .......................................................... 35 1.3.2.1 Signaling through the lymphotoxin beta receptor is required for HEV differentiation ......... 36 1.3.2.2 Post-translational modifications are required for L-selectin recognition of PNAd ............... 37 1.3.2.2.1 Sulfation ........................................................................................................................... 39 1.3.2.2.2 Glycosylation .................................................................................................................... 40 1.3.3 Markers of high endothelial venules .............................................................. 40 1.3.4 Immune Cell Recruitment by HEV ................................................................. 40 1.3.5 Tertiary Lymphoid Organs ............................................................................. 41 1.3.5.1 TLS in Cancer ..................................................................................................................... 43 1.3.5.1.1 Lung Cancer ..................................................................................................................... 44 1.3.5.1.2 Skin cancers ..................................................................................................................... 45 1.3.5.1.3 Colon Cancer ................................................................................................................... 46 1.3.5.2 Therapeutic induction of TLS .............................................................................................. 46 1.3.6 Future Perspectives ....................................................................................... 46 1.4. THE IL-36 CYTOKINE SUBFAMILY IN IMMUNE-MEDIATED PATHOGENESIS ................................................................................................................................... 47 vii 1.4.1 The IL-36 cytokines share unique characteristics with other IL-1 family cytokines ................................................................................................................. 48 1.4.2. IL-36R signaling ............................................................................................ 49 1.4.3 IL-36 as an Early Inflammatory Mediator of Lymphoid Organogenesis in Tissues, Including Cancer ...................................................................................... 52 2.0. TBET AND IL-36γ COOPERATE IN THERAPEUTIC DC-MEDIATED PROMOTION OF ECTOPIC LYMPHOID ORGANOGENESIS IN THE TME ....................................... 56 2.1 ABSTRACT ......................................................................................................... 57 2.2 INTRODUCTION ................................................................................................. 58
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