Multifaceted Role of IL-1 in Cancer and Inflammation

Multifaceted Role of IL-1 in Cancer and Inflammation summarizes the existing literature and discusses future perspectives about the role of IL-1 in immune suppression, cancer progression, angiogenesis, and resistance to immunotherapies. The book presents mechanisms to overcome IL-1 mediated immune suppression in tumor microenvironment and covers topics on the source of IL-1 in the tumor microenvironment, IL-1 mediated downstream pathway, mechanism of IL-1 mediated immune suppression in cancer, and its effect on immunotherapy of cancer. Those topics help readers understand the effect of IL-1 on cancer immunopathology and immunotherapy, and provide them with broader concepts to develop therapies for IL-1 enrichment tumors.

This is a valuable source for cancer researchers, clinicians and other members of the biomedical field who wants to learn more about mechanisms to improve outcome of cancer immunotherapies.

• Presents a summary in the beginning of each chapter to help readers to find the needed information and understand the content easily
• Encompasses detailed schematic diagrams and illustrations throughout the content to explain the complex immune mechanisms discussed
• Discusses future perspectives in all chapters to motivate researchers to work on emerging problems
• Includes contributions from internationally renown experts sharing their experiences on clinics and research

• Language: English
• Publisher: Academic Press
• Release date: Jun 7, 2023
• ISBN: 9780323859677

Book preview

Multifaceted Role of IL-1 in Cancer and Inflammation

Editor

Manisha Singh

Department of Gastrointestinal (GI) Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States

Table of Contents

Cover image

Title page

Copyright

List of contributors

Preface

Chapter 1. Role of IL-1 gene polymorphisms in common solid cancers

Introduction

Role of IL-1 in cancer initiation, progression, and immunosuppression

The interleukin-1 gene cluster: structure and genetic polymorphisms

IL1A, IL1B, and IL1RN polymorphism in various cancers

Conclusion

Abbreviations

Chapter 2. The role of IL-1 in tumor growth and angiogenesis

Introduction

Concluding remarks

Chapter 3. Interleukin-1-mediated immune suppression and resistance to immunotherapy in cancer

Introduction

Induction of IL-1 in the tumor microenvironment

IL-1-mediated immune suppression and resistance to immunotherapy

Conclusions and future perspectives

Chapter 4. Strategies to overcome interleukin-1-mediated immune suppression and resistance to immunotherapy in cancer

Introduction

IL-1 biology

IL-1's role in resistance to immunotherapy

Future perspectives

Chapter 5. Modulation of IL-1-mediated inflammation in cancer using a food-based approach: a preventive strategy

Introduction

IL-1-mediated cancer prognosis

IL-1 in human health and disease

Therapeutic targeting of IL-1 through dietary bioactive compounds

Conclusion

Chapter 6. IL-1-mediated inflammation in COVID-19

Introduction

Interleukin-1

Protective and pathologic roles of IL-1 in viral diseases

COVID-19: general introduction

Respiratory distress and cytokine storm

Immunomodulatory drugs and COVID-19 infection

Conclusion and future perspectives

Chapter 7. Role of IL-1 in bacterial infections

Introduction

Role of IL-1 in immunity

IL-1α

IL-1β

IL-1 in bacterial infections

IL-1 signaling and pathways involved

IL-1 polymorphism associated with bacterial diseases

IL-1 immunotherapy

Concluding remarks

Index

Copyright

Academic Press is an imprint of Elsevier

125 London Wall, London EC2Y 5AS, United Kingdom

525 B Street, Suite 1650, San Diego, CA 92101, United States

50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States

The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom

Copyright © 2023 Elsevier Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.

To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

ISBN: 978-0-12-824273-5

For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Stacy Masucci

Acquisitions Editor: Linda Versteeg-Buschman

Editorial Project Manager: Pat Gonzalez

Production Project Manager: Swapna Srinivasan

Cover Designer: Miles Hitchen

Typeset by TNQ Technologies

List of contributors

Sadhna Aggarwal,     Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States

Avadhesh,     Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India

Kinjal Bhadresha,     Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States

Sagar Dholariya,     Department of Biochemistry, All India Institute of Medical Sciences, Rajkot, Gujarat, India

Shweta Dubey,     Amity Institute of Virology and Immunology, Amity University Uttar Pradesh (AUUP), Noida, Uttar Pradesh, India

Ankita Garg,     Department of Infectious Diseases, College of Veterinary Medicine, The University of Georgia, Athens, GA, United States

Smriti Gaur,     Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Uttar Pradesh, India

Subash C. Gupta

Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India

Department of Biochemistry, All India Institute of Medical Sciences, Guwahati, Assam, India

Preeti Jain,     SK College, Somaiya Vidyavihar University, Mumbai, Maharashtra, India

Deepak Parchwani,     Department of Biochemistry, All India Institute of Medical Sciences, Rajkot, Gujarat, India

Abhishek Puthenveetil,     Laboratory of Molecular and Applied Immunology, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel

Aishwarya Rani,     Amity Institute of Virology and Immunology, Amity University Uttar Pradesh, Noida, Uttar Pradesh, India

Anusmita Shekher,     Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India

Pradeep K. Shukla,     Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States

Baldeep Singh,     Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India

Manisha Singh,     Department of Gastrointestinal (GI) Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States

Pratibha Singh,     Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United States

Ragini D. Singh,     Department of Biochemistry, All India Institute of Medical Sciences, Rajkot, Gujarat, India

Shubhi Singh,     Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Uttar Pradesh, India

Devinder Toor,     Amity Institute of Virology and Immunology, Amity University Uttar Pradesh, Noida, Uttar Pradesh, India

Preface

I am a passionate scientist devoted to discovering cancer-curing drugs. While working on a mouse melanoma model, I observed that tumor size was inversely correlated with response to immunotherapy. Notably, an increased level of IL-1 in large tumors induces an immune-suppressive microenvironment and makes them resistant to immunotherapy via accumulation of polymorphonuclear myeloid-derived suppressor cells. The results of this study were published. However, my curiosity led me to ask more questions about IL-1-mediated immune suppression in tumor microenvironment such as the source of IL-1 in the tumor, the mechanism of immune suppression through IL-1, the immune-suppressive effects of IL-1 on other tumors and coronavirus infection, and the role of microbiomes in IL-1 modulation. These questions are the foundation for this book. The other authors and I summarized published findings and our opinions about the role of IL-1 in tumor progression, angiogenesis, and immune suppression and strategies to overcome IL-1-mediated resistance to cancer immunotherapy.

I am deeply indebted to God, family, friends, and teachers for their blessings and support throughout my career.

Manisha Singh

Department of Gastrointestinal (GI) Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States

Chapter 1: Role of IL-1 gene polymorphisms in common solid cancers

Ragini D. Singh ¹ , Sagar Dholariya ¹ , Anusmita Shekher ² , Avadhesh ² , Deepak Parchwani ¹ , and Subash C. Gupta ² , ³       ¹ Department of Biochemistry, All India Institute of Medical Sciences, Rajkot, Gujarat, India      ² Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India      ³ Department of Biochemistry, All India Institute of Medical Sciences, Guwahati, Assam, India

Abstract

Because of the strong association of inflammation with cancer, the master cytokine, interleukin-1 (IL-1), has been extensively researched for its role in carcinogenesis. An appropriate, limited, targeted inflammatory response may provide protection to the host. However, on the other hand, an unusually protracted or severe inflammatory response may generate a microenvironment conducive to carcinogenesis. Inherited variants in the IL-1 gene affect its expression and eventually the molecular physiology of the IL-1 system. Studies have reported a wide variety of genetic variations inside the IL-1 gene cluster. Also, interpopulation differences in the distribution of polymorphic IL-1 genotypes are widespread. The polymorphic forms exert effects on cancer risk, development, and progression. This chapter focuses on the structure of the IL-1 gene, the polymorphisms reported in the IL-1 prototypes, i.e., IL1A, IL1B, and IL1RN, and the current knowledge on the involvement of polymorphic forms of IL-1 prototypes in cancer predisposition and prognosis, with particular emphasis on solid tumors.

Keywords

Cancer; Cytokines; Inflammation; Interleukin; Polymorphism

Introduction

During the last 2 decades, the contribution of chronic inflammation as a significant driver of carcinogenesis and the involvement of cytokines in cancer formation, progression, and metastasis, as well as their value as therapeutic agents and targets, has gained enormous interest [1]. Additionally, researchers have expended considerable effort to identify variations in cytokine genes [2], specifically in the master cytokine, proinflammatory interleukin-1 (IL-1), which may contribute to or influence individuals' susceptibility to cancer and the clinical course of various malignancies. The literature concerning IL-1 gene polymorphism and cancer is rapidly growing due to the development of robust molecular genotyping techniques, which have led to the identification of many novel cytokine polymorphisms. The mechanisms underlying the impact of the IL-1 genetic polymorphisms on cancer susceptibility are very complex. The actual effect of polymorphism on gene expression and cancer susceptibility varies depending on the location and type of polymorphism [3]. Any variation in the IL-1 genetic sequence may affect the IL-1 cytokine protein expression, stability, and function (receptor interaction) [4]. This may cause a shift or divergence in the timely and synchronized actions required between a proinflammatory signal (mediated by the agonists, IL-1A and IL-1B) and its termination and resolution (mediated by the antagonist, IL-1RN). Eventually, this could result in an excess proinflammatory signal, hyperinflammation, and cancer susceptibility [4].

This chapter summarizes the significance of IL-1 in cancer initiation, progression, and immunosuppression, followed by a discussion of the structure and significant polymorphisms studied in the prototype IL-1 molecules, IL1α/1A, IL1β/1B, and IL-1RN. Later in the chapter, we address the impact of these polymorphisms on individuals' susceptibility to various solid tumors and the implications of these genetic variations on the prognosis and survival of cancer patients.

Role of IL-1 in cancer initiation, progression, and immunosuppression

Clinical and epidemiological observations strongly support the hypothesis that chronic inflammation enhances susceptibility to cancer formation and promotes all stages of tumorigenesis [4–8]. Chronic inflammation sustained by infection, viral or bacterial or inflammatory conditions of diverse origins, prolonged exposure to radiation, or an environmental carcinogenic pollutant frequently precedes cancer development [9].

Notable is the involvement of IL-1, the master proinflammatory cytokine, as the primary mediator of both local and systemic inflammation [8]. IL-1 exerts its critical functions in all the phases of malignant processes. It not only promotes the initiation of cellular transformation but also influences the tumor microenvironment (TME) and tumor progression. This cytokine can be secreted by host cells (immune cells and stromal cells) or tumor microenvironment cells or malignant cells, at any stage of the process, (i) as a part of the inflammatory reaction preceding and accompanying tumor growth and (ii) in reaction to substances secreted by the transformed cells. The concentration of IL-1 secreted may depend upon the inherent variations in the pattern of cytokine gene expression in malignant cells [9]. The target cells of the cytokine include premalignant cells as well as the cells of the tumor microenvironment.

The mechanism by which IL-1 mediates tumorigenesis is complex and yet to be fully elucidated [10]. However, the fundamental experimental evidence for the function and involvement of IL-1 in the carcinogenesis process came from mouse models lacking both proinflammatory cytokines and their signaling components. These models formed the basis for understanding the role of the IL-1 family in carcinogenesis. They provided evidence that (i) supraphysiological levels of IL-1 can promote inflammation-mediated tumorigenesis, and (ii) local cytokine expression, their network, and their interrelationship (net cytokine effect) play a significant role at various stages of carcinogenesis [11].

IL-1 may contribute to the early stages of cancer [12] by impacting immune, epithelial, and premalignant cells and priming them to release redox molecules, reactive oxygen species, nitric oxide, and local IL-1. This contributes to the initial mutagenic event, and their continous release could further exacerbate the carcinogenic process by stimulating premalignant cell proliferation through autocrine and paracrine signaling [9]. There is a dearth of data on the involvement of IL-1 molecules as inducers of carcinogenesis. However, there are abundant studies on its role in the invasiveness of the existing altered/transformed cells. Studies have provided evidence that secreted IL-1 from malignant cells/TME cells, or tumor stromal cells are essential perpetrators of inflammatory factors [12]. They may play a role in controlling tumor progression [13]. However, the mechanisms through which IL-1 promotes angiogenesis and metastasis are complicated [10]. IL-1 acts as a master cytokine and focal point for the convergence of several angiogenic and metastatic stimuli [9]. IL-1 stimulates the production and secretion of matrix metalloproteinase (MMP) and angiogenic factors, namely, vascular endothelial growth factor (VEGF), basic fibroblast growth factor, chemokine (C-X-C motif) and IL-8 [9,14]. It plays a synergistic proangiogenic role with VEGF [15] and has complex effects on endothelial cell (EC) physiology. IL-1 plays a predominant role in activating ECs in a prothrombotic/proinflammatory direction and significantly alters the gene expression and function of ECs. It causes induction of expression of various proinflammatory cytokines, and adhesion molecules, in ECs [8,10]. IL-1 can also upregulate the growth factor and inflammatory cytokine gene signatures through nuclear factor of activated T-cells and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) signaling [16].

In vivo studies have indicated that both the agonist molecules, IL-1A and IL-1B, play a significant role in cancer progression [15]. Their increased expression during genotoxic stress promotes VEGF expression [17–20]. IL-1B with VEGF aids in the maturation of endothelial progenitor cells and increases the permeability of ECs through the Src-dependent pathway [21]. IL-1A, on the other hand, (i) recruits macrophages, which are a rich source of fibroblast growth factors, chemokines, and other inflammatory cells that express VEGF [22,23], and (ii) promotes macrophage infiltration and their activation at local tumor sites. This has an effect on the angiogenic cascade through the production of proteolytic enzymes, cytokines, and growth factors [9], and (iii) it stimulates ECs to produce IL-8, a proangiogenic cytokine [10], and promotes induction of chemokine ligand 1 (CXCL-1), and adhesion molecules, vascular cell adhesion molecule 1, and intracellular adhesion molecule 1, and thus increases transendothelial migration of inflammatory cells.

Additionally, there is also evidence of a strong significant correlation between IL-1A and IL-1B expression in distant metastases [13,24–26]. IL-1α stimulates the expression of prometastatic genes in stromal fibroblasts, MMP-3, IL-6, IL-8, and in malignant cells, IL-6 and IL-8, in an autocrine and paracrine fashion [27]. IL-1α also promotes adhesion and invasion into laminin (Fig. 1.1).

Massive inflammation concomitantly induces immunosuppression. IL-1 generated from tumor cells recruits myeloid cells, which includes myeloid-derived suppressor cells (MDSCs), tumor-associated neutrophils, and M2-like phenotype tumor-associated macrophages. IL-1β acts as an essential stimulus for MDSC expansion and propagation via cyclooxygenase-2 (COX-2) and prostaglandins. These cells provide an increase in IL-1 concentration in the microenvironment and create a nurturing niche for cancer stem cells, thus promoting tumor progression through IL-1 [8] (Fig. 1.1).

Figure 1.1  Role of IL-1 in tumor biology. Adapted from Gelfo V, Romaniello D, Mazzeschi M, et al. Roles of IL-1 in cancer: from tumor progression to resistance to targeted therapies. Int J Mol Sci 2020;21:6009.

The interleukin-1 gene cluster: structure and genetic polymorphisms

The IL-1 genes are clustered in an ∼500-kb region of the chromosomal band 2q.14. IL-1A/α and IL-1B/β (closely located) and IL-1RN are the prototypical members of the IL-1 gene family. IL-1A and IL1-B, both agonists for the cell membrane IL-1 type I receptor, encode proinflammatory cytokines, IL-1α and IL-1β, respectively. In contrast, the gene IL-1RN encodes the IL-1 receptor antagonist (IL-1RA), a nonsignaling, antiinflammatory molecule that competes with IL-1α and IL-1β for receptor binding [28,29] (Fig. 1.2).

The prototypic members have acquired several coding, noncoding, and control sequence variations [4]. These include single nucleotide polymorphisms (SNPs), insertion/deletion, and a variable number of tandem repeat polymorphisms (VNTRs). The variations may have an impact on mRNA stability and degradation [30], processing, maturation, function, and posttranslational modifications of proteins [31]. Collectively, any variation in the IL-1 gene sequence may disturb the fine, timely, and coordinated balance between proinflammatory and antiinflammatory signals. This may result in a build-up of proinflammatory signals, hyperinflammation, and an increased risk of malignancy [4]. Changes in the balance of agonist and antagonist molecules due to genetic variations can also have an effect on clinicopathological characteristics and prognosis of cancer [32].

This section presents the gene structure of the prototypic members (IL-1A, IL-1B, and IL-1RN) and their frequent polymorphisms seen/studied along with their functional relevance.

The interleukin 1A (IL-1A/IL-1α) gene: structure and genetic polymorphisms

IL-1A is a 10.2-kb gene located on chromosome 2q. It contains seven exons and six introns [33]. The first exon encodes the 5′ untranslated region (UTR), while the second, third, and fourth exons encode the enzymatic hydrolysis region of the proprotein, the fifth, sixth, and seventh exons encode IL-1α, and the seventh exon encodes the 3′ UTR [34]. The promoter is devoid of the canonical regulatory regions, i.e., the TATA and CAAT box motifs [35]. Variable transcription factors such as Specificity protein-1 (Sp1), Activator protein-1 (AP1), and NF-κB [36] affect human IL-A gene expression. Presently, 148 SNPs have been identified in this gene. Among the 148 SNPs reported, the most extensively investigated variations that are believed to have a functional role include the following: SNP:rs1800587, SNP:rs17561, and SNP:rs3783553 [34] (Fig. 1.3).