Vaccines for Cancer Immunotherapy: An Evidence-Based Review on Current Status and Future Perspectives

By Nima Rezaei

Therapeutic cancer vaccines represent a type of active cancer immunotherapy. Clinicians, scientists, and researchers working on cancer treatment require evidence-based and up-to-date resources relating to therapeutic cancer vaccines. Vaccines for Cancer Immunotherapy provides a reference for cancer treatment for clinicians and presents a well-organized resource for determining high-potential research areas. The book considers that this promising modality can be made more feasible as a treatment for cancer. Chapters cover cancer immunology, general approaches to cancer immunotherapy, vaccines, tumor antigens, the strategy of allogeneic and autologous cancer vaccines, personalized vaccines, whole-tumor antigen vaccines, protein and peptide vaccines, dendritic cell vaccines, genetic vaccines, candidate cancers for vaccination, obstacles to developing therapeutic cancer vaccines, combination therapy, future perspectives and concluding remarks on therapeutic cancer vaccines.

• Introduces the feasible immunotherapeutic vaccines for patients with different types of cancer
• Presents the status of past and current vaccines for cancer treatment
• Considers advantages and disadvantages of different therapeutic cancer vaccines
• Looks at the combination of vaccines and other modalities, including immunotherapeutic and conventional methods
• Analyzes obstacles to development of therapeutic cancer vaccines
• Gives a view on future perspectives in the application of therapeutic cancer vaccines

• Language: English
• Publisher: Academic Press
• Release date: Oct 17, 2018
• ISBN: 9780128140406

Book preview

Vaccines for Cancer Immunotherapy

An Evidence-Based Review on Current Status and Future Perspectives

Nima Rezaei

Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran

Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran

Mahsa Keshavarz-Fathi

School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran

Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran

Table of Contents

Cover image

Title page

Copyright

List of Contributors

Preface

Chapter 1. Cancer Immunology

Innate and Adoptive Immunity

Activating Immune Cells

Inhibitory Immune Cells

Immunoediting Hypothesis

Chapter 2. Immunotherapeutic Approaches in Cancer

History

Approaches of Cancer Immunotherapy

Passive Versus Active Immunotherapy

Mechanism-Based Immunotherapies: Interactions Between Tumor Cells and the Immune System

Chapter 3. Vaccines, Adjuvants, and Delivery Systems

Definition and Classification

Cancer Vaccine

Adjuvants

Vectors and Delivery System

Route of Administration

Chapter 4. Tumor Antigens

Introduction

Identification of Tumor Antigens

Overexpressed proteins and mutated antigens in tumor cells

Epitope Spreading

Tumor-Associated Antigens

Tumor-Specific Antigens

Neoantigens

Glycolipids and Glycoproteins as Antigens

Mono-Epitope Versus Poly-Epitope Antigen

Chapter 5. Strategy of Allogeneic and Autologous Cancer Vaccines

Autologous Cancer Vaccines

In Vivo Studies and Clinical Implications

Allogeneic Cancer Vaccines

In Vitro/In Vivo Studies and Clinical Implications

Chapter 6. Personalized Cancer Vaccine

Introduction on Personalized Medicine

Personalized Medicine in Cancer Patients

Neoantigens and Personalized Cancer Vaccines

Personalized Cancer Vaccines in Clinical Studies

Chapter 7. Whole Tumor Cell Vaccine for Cancer

Tumor Cell Lysates

Tumor-Derived Exosomes

Irradiated Gene-Modified Tumor Cell Vaccine

Clinical Trials

Approved Vaccine

Advantages and Disadvantages

Optimization

Chapter 8. Peptide and Protein Vaccines for Cancer

Peptide-Based Vaccine

Protein-Based Vaccine

Mechanism of Action

Clinical Trials

Advantages and Disadvantages

Optimization

Chapter 9. Immune Cell Vaccine for Cancer

Immune Cell Vaccine

Mechanism of Action

Clinical Trials

Approved Vaccine

Advantages and Disadvantages

Optimization

Chapter 10. Genetic Vaccine for Cancer

Mechanism of Action

DNA Vaccine

RNA Vaccine

Adverse Effects

Advantages and Disadvantages

Optimization

Chapter 11. Candidate Cancers for Vaccination

Vaccines for Prostate Cancer

Vaccines for Melanoma

Vaccines for Lung Cancer

Vaccines for Colorectal Cancer

Vaccines for Breast Cancer

Chapter 12. Obstacles in the Development of Therapeutic Cancer Vaccines

Tumor Antigens

Tumor Burden

Clinical Response Versus Immune Response

Prior Treatments

Designing Clinical Trials

Chapter 13. Combination Therapy: Cancer Vaccines and Other Therapeutics

Chemotherapy Combined With Vaccines

Radiation Combined With Vaccines

Targeted Therapies Combined With Immunotherapy

Hormone Therapy Combined With Vaccine

Vaccine Combined With Other Immunotherapeutic Modalities

Chapter 14. Concluding Remarks and Future Perspectives on Therapeutic Cancer Vaccines

Concluding Remarks

Basic Immunology of Cancer Vaccines

Approved Vaccines

Neoantigen Vaccines

Preventive Cancer Vaccine

Considerations to Fulfill Ambitions

Index

Copyright

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List of Contributors

Mahsa Keshavarz-Fathi

School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran

Sepideh Razi

Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran

Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

Nima Rezaei

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran

Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran

Saeed Farajzadeh Valilou,     Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran

Preface

A long time ago, infectious diseases were a major health problem threatening human life. This led to several epidemics and pandemics and resulted in a high mortality rate. Antibiotics and vaccines were lifesaving agents that contributed to the evolution of treatment and the prevention of infectious diseases. Nowadays, lots of infectious diseases are being bridled by the application of these approaches; therefore, the focus of health has shifted toward noninfectious diseases such as cancer. Cancer is a rebellious disease originating from self-cells, which possess some characteristics similar to those of normal cells. This can complicate targeting cancerous cells without causing severe side effects. Biologic targeted therapies were developed to yield a specific directed response against tumor cells. Because they aim to influence only cells containing specific targets, this approach is safer than that of toxic agents. Although immunotherapy can be applied in both targeted and unspecific manners, designing therapeutics able to induce immune responses, which single out tumor cells, theoretically results in yielding better outcomes indicative of efficacy and safety. As expected, practice does not always follow the theory. Therefore, a number of clinical evaluations are required to assess the efficacy and safety of the therapeutic alone or compared with other standards of care.

Vaccines, which were originally known as a preventive approach to infectious diseases, have become attractive immunotherapies for cancers in both the preventive and therapeutic settings. These modalities evoking active and specific immune responses aim to improve clinical outcomes besides enhancing immunological indicators of response. Many attempts have been made to assess vaccines for cancer and improve their efficacy. Over the years, cancer vaccines have had several ups and downs. Some cases of success and some of failure were recorded in their history, leading to lessons on optimizing the modality and picking the best population and combination. Vaccines are attractive therapeutics because of promising results obtained with certain vaccines in certain cancers. Advances in genomic technologies have also promoted the status of personalized vaccines for cancers and have yielded positive clinical outcomes with vaccines alone and combined with immune checkpoint blockers. The field of cancer vaccines is moving forward; a look at the background, history, and current state, which are provided in this book, assists in the development of vaccines and provides future perspectives for this modality. In this book, we first explain the immunology of cancer and immunotherapeutics applied and approved for cancer (Chapters 1 and 2). Afterwards, types of vaccines, adjuvants, and delivery systems (Chapter 3) are examined. Next, tumor antigens as targets for vaccine therapy (Chapter 4) and approaches implemented to design autologous, allogeneic and personalized vaccines (Chapters 5 and 6) are reviewed. The following sections provide various types of therapeutic vaccines, their clinical applications and efficacy (Chapters 7–10), examples of vaccines for various types of cancers and candidates for vaccine therapy (Chapter 11), hurdles in the way of cancer vaccine development (Chapter 12), combination therapy (Chapter 13), and concluding remarks and future perspectives (Chapter 14).

We hope that this book will be welcomed not only by clinicians but also by basic scientists who wish to have an update in this field.

Nima Rezaei, MD, PhD

[e-mail]

Mahsa Keshavarz-Fathi, MD

[e-mail]

Chapter 1

Cancer Immunology

Mahsa Keshavarz-Fathi ¹ , ² , ³ , and Nima Rezaei ³ , ⁴ , ⁵       ¹ School of Medicine, Tehran University of Medical Sciences, Tehran, Iran      ² Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran      ³ Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran      ⁴ Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran      ⁵ Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran

Abstract

To understand the fundamental interactions between tumor cells and the immune system, immunosurveillance and evolutionally immunoediting hypothesis were proposed. When tumor cells overcome mechanisms of the immune system in the elimination phase, they proceed with the equilibrium and probably escape phases. In each phase, various immune cells and cytokines are involved. Moreover, several mechanisms are considered for the tumor escaping form the immune system, including defect in tumor antigen presentation and recognition, dominance of inhibitory mechanisms and lack of activating effects, and resistant subtypes of tumor cells such as cancer stem cells. In this chapter, various immune cells, which play a role in the immune response against tumor cells and immunoediting hypothesis, will be reviewed.

Keywords

Adaptive immunity; Cytokines; DCs; Elimination; Equilibrium; Escape; Immunoediting; Innate immunity; Lymphocytes; Macrophages; MDSCs; NK cells; Tregs

Innate and Adoptive Immunity

Pathogens and endogenous dangerous mutated and cancerous cells must be distinguished and destroyed by the immune system, which has two main arms: innate and adaptive immunity. Each arm has its own specialized cell-based and humoral responses. The first responder to exogenous and endogenous threats is the innate immune system, which operates as a nonspecific arm and rapidly acts through pattern recognition receptors (PRRs). These receptors are located on the surface of innate cells including tissue-resident cells such as macrophages, dendritic cells (DCs), monocytes, and neutrophils, which circulate in the blood. Most of the PRRs bind to the pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) to recognize the potential danger. ¹,² Toll-like receptors (TLRs) are one of the significant PRRs, present on the surface of antigen-presenting cells (APCs), such as DCs. By recognition of PAMPs and DAMPs, they initiate activation of the signaling pathways such as transcription factor nuclear factor-kappa B (NF-κB) and interferon regulatory transcription factor, which are inflammatory and induce type I interferons and cytokines to recruit and activate lymphocytes. ³,⁴

The innate immune system is not capable of forming an immunological memory. Therefore, the role of the adaptive immune system in providing immunological memory and specific responses is manifest. Adaptive immune cells are capable of recognizing a single specific antigen because each lymphocyte, before facing any antigen, carries only one receptor, which is specific for one antigen. Therefore, to cover recognition of the variety of antigens, which the immune system meets through its lifespan, millions of antigen-specific receptors must exist. In order to provide this vast variety, the genes of variable chains of the receptors randomly recombine during development of lymphocytes in the central lymphoid organs, the bone marrow, and thymus. Then, various variable chains are paired to create the whole lymphocyte receptor repertoire of a person. ⁵

Clonal selection of lymphocytes is the central feature of the adaptive immune system, which leads to developing specific responses. As described earlier, lymphocytes bear a variety of receptors specific for different antigens, named antigen-specific receptors. These cells are activated and proliferated only after exposure to the specific antigens. The receptor of a lymphocyte's descendants, i.e., the effector cells, are the same with their ancestor's, and this is the concept of a clone. Clonal deletion is also crucial to omit autoreactive lymphocytes, which respond to the self-antigens. ⁵

To induce an immune response against cancer, two central phases are performed, i.e., the priming and effector phases. In the first phase, the APCs such as DCs prime the T cells. They obtain the tumor antigens of dying cancer cells. If a danger signal is not available, immune tolerance toward the antigen is induced. Immunogenic cell death is responsible to generate danger signals, which are recognized by PRRs on DCs. The stress induced during cell death leads to providing danger signals such as type I interferons, chemokine ligand 10 (CXCL10), CXC‑chemokine receptor 3 (CXCR3), heat shock protein 70 kDa (HSP70), and HSP90. The danger signals function as adjuvants to increase the immunogenicity. ⁶ Antigens and danger signals lead to the maturation of DCs, and then they travel toward the draining lymph nodes. ⁶ To induce effector T cells, DCs transduce three signals to T cells. The first signal is transduced through antigen presentation by the major histocompatibility (MHC) molecules on DCs to T cell receptors (TCRs) on the T cells. The second signal results from costimulatory or coinhibitory molecules. The second signal adjusts and modulates the type of immune response against the danger signal. Following these signals, in the third signal a number of cytokines are produced to direct the type of following immune response. ⁷ The type of DC maturation affects on determining the phenotype of T cells (Fig. 1.1). As a consequence of priming, CD4+ and CD8+ effector T cells, necessary to evoke a robust immune response, are developed. Cytotoxic T lymphocytes, which are CD8+ T cells, are the main effector cells to destroy the tumor cells. However, CD4+ T cells are required for optimal and long-lived effector CD8+ T cells and for induction and maintenance of CD8+ memory cells. ⁸,⁹

Antigens are processed through two different mechanisms. MHC-I restricted peptides undergo the proteasome dependent mechanism. The proteasome changes the long peptides to small peptides containing 9–15 amino acids, to be delivered to the endoplasmic reticulum (ER) via the transporter of antigen processing (TAP). In the ER, the peptides with 9–12 amino acids bind to the MHC-I molecules to be transported to the surface of cells. The MHC-II restricted peptides use the endosomal system. Cathepsins process the antigens in endosomes, and peptides with 12–15 amino acids bind to the MHC-II, which are transported to the surface of DCs. ¹⁰

There are some barriers that hamper the function of effector T cells. Immunosuppressive phenotype of tumor microenvironment is one of the barriers generated due to the function of some immune cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as well as the cytokines, chemokines, and indoleamine 2,3-dioxygenase (IDO) secreted by the tumor cells. ¹¹–¹⁴

Activating Immune Cells

In both arms of the immune system there are immune cells and cytokines in favor of antitumor responses as well as inhibitory components, which hamper effective and robust responses against cancer. The interplay between tumor cells and these activating and inhibitory components is one of the factors determining the final dominancy of tumor cells or the immune response. Herein, we will first review the activating components and then the inhibitory building blocks of the immune response against cancer.

Figure 1.1 The effect of DC maturation on the phenotype of T cells.Based on the various PAMPs and tissue factors, DCs may undergo one of the maturation processes including immunogenic, inflammatory, and tolerogenic maturation. Immunogenic maturation of DCs, induced by microbial components and type 1 tissue factors, which results in development of Th1 cells. Proinflammatory factors leading to inflammatory maturation of DCs give rise to Th2 and Treg cells. Both tolerogenic and immature DCs can induce Treg cells. CCR, CC-chemokine receptor; DC, dendritic cell; IFN, interferon; IL, interleukin; PGE2, prostaglandin E2; TGF-β, transforming-growth factor-β; Th, T helper; Treg, T regulatory; TSLP, thymic stromal lymphopoietin.

Mature DCs

Mature DCs consist of two main subtypes, classical DCs (cDCs), also known as myeloid DCs (mDCs), and the second subtype, plasmacytoid DCs (pDCs). In the blood, a great number of DCs are pDCs, which play role in the antiviral immune response through secretion of type I interferons. ¹⁵

There are different subsets of cDCs as well. Although CD141+ DCs are classic DCs playing an important role in cross-presentation of tumor antigens and priming of immune response against tumor, ¹⁶ all DCs, resident in lymphoid organs, such as CD141+/BDCA3+, CD1c+/BDCA1+, or plasmacytoid can do cross-presentation. ¹⁷ CD1a+ DCs, which are the major subsets of cDCs, and CD14+ DCs, with the monocyte-related phenotype, are present in the dermis layer of the human skin, whereas another self-renewing subtype of DCs known as Langerhans cell (LC) exists in the epidermis. ¹⁸ CD14+ DCs are responsible for the induction of humoral immunity, while LCs are responsible for priming of CD8+ T cells, and CD1a+ DCs perform this action as well but they are less potent in comparison to LCs. ¹⁹

T cell priming function of DCs is initiated with presentation of MHC-peptide complexes to DCs. Costimulatory molecules on APCs and activating cytokines by T cells are subsequently produced. ²⁰ The mentioned features determine the maturation of DCs and their direction toward antitumor immunity.

Several cytokines are produced by DCs as well. IFNs, tumor necrosis factor-α (TNF-α), interleukin 1 (IL-1), IL-6, IL-12, and IL-23 are among the cytokines secreted by DCs, which regulate T cell responses. ²¹ Transforming growth factor β (TGFβ), and IL-10, secreted by immature DCs, demonstrate an inhibitory effect on T cell responses and thus prevent tumor destruction. ²²

Classically Activated Macrophages (M1)

In the tumor microenvironment, macrophages can exert both anti- and protumoral roles. Their function is dependent on their phenotype developed by the effects of intracellular interplays and two main sets of cytokines. ²³ Macrophages originate from immature myeloid precursors or circulating monocytes recruited into the tumor site through chemokines such as CCL2, CCL5, and CXCL12. ²⁴,²⁵

Classically activated macrophages or M1 phenotype are developed under influence of cytokines such as GM-CSF, IFN-γ, and TLR agonists. ²⁶ They play antitumoral and inflammatory roles in the tumor microenvironment by various means, including phagocytosis, antigen presentation, production of proinflammatory cytokines, and cytotoxic effects. They use reactive oxygen species (ROS), reactive nitrogen species (RNS), IL-1β and TNF-α to perform cytotoxic activities. ²⁷ M1 macrophages produce IL-12, which promotes antitumor responses of natural killer (NK) cells and T cells by production of IFN-γ. M1 macrophages themselves are capable of production of IFN-γ as well. ²⁸,²⁹

Granulocytes

Granulocytes, as the agents of the innate immune system, which mediate inflammation, take part in the first steps of immune response against tumors. They are cytotoxic operators that act through release of substances such as inflammatory cytokines, ROS, cathepsin G, and azurocidin. ³⁰ They may also play a role in cancer progression by induction of angiogenesis and metastasis. ³¹

Neutrophils by using ROS and Fas/Fas ligand act as an antitumor immune cell. Eosinophils were observed in many cancer types specimens, while their anti- or protumoral activities are not obvious. ²⁷ Basophils are the third type of granulocytes, which mainly have a role in allergic reactions. However, they have effects on antitumor immune response and act as APCs as well. ³²

Interestingly, granulocytes are among the significant effectors activated in responses to DNA vaccine. Moreover, there are reports of the associations between the dense infiltration of granulocytes and clinical responses to Bacillus Calmette-Guérin and autologous cancer cell vaccines secreting GM-CSF. ³³–³⁵

B Lymphocytes

B lymphocytes are the cells of adaptive immune system, which have either anti- or protumoral activities. They are capable of producing not only antibodies (Abs) targeting tumor antigens but also cytokines, which play a role in T cell functions. The antitumorigenic B cells have direct cytotoxic effect by release of granzyme B and indirect functions against cancer through antibody-dependent cell cytotoxicity and complement-dependent cytotoxicity, which both are mediated by antibodies secreted from B cells. ³⁶

They can also act as APCs in tumor microenvironment in case of failure of DCs in antigen presentation. The presence of B cells along with CD8+ T cells has been reported as a positive prognostic factor for survival of patients with ovarian cancer. ³⁷

T Helper Lymphocytes

T cells are the next cells of the immune system. They are divided into classical or αβ T cells and γδ T cells. The classical T cells have two main classes; i.e., CD4+ or T helper cells, often recognizing peptides presented by MHC-I, and CD8+ or cytotoxic T cells, which recognize peptides presented by MHC-II. MHC class I is located on the surface of all nucleated cells, and MHC class II is located only on APCs. ³⁸

According to the cytokines in tumor microenvironment, different types of CD4+ effector cells are originated from naïve CD4+ T cells. T helper (Th) cells are one of the routine kinds of this differentiation. Th1 cells are involved in cell-mediated immune responses developed by production of the cytokines such as IFN-γ, and Th2 cells are responsible for humoral or antibody dependent responses, which are developed by production of cytokines such as IL-4, IL-5, and IL-13. ³⁹ Both Th1 and Th2 cells are involved in antitumor immunity. However, Th1 dominant immunity is vital for developing memory, which is required for providing a specific cytotoxic antitumor response. ⁴⁰ IL-17+ T cells are CD4+ (Th17) or CD8+ (Tc17) T cells, which secrete IL-17. Both pro- and antitumor effects have been reported for IL-17+ cells. ²⁷,⁴¹

Cytotoxic T Lymphocytes

CD8+ T cells are the cytotoxic agents of the adaptive immunity. They destroy tumor cells after they are activated by APCs. After termination of cytotoxic functions, programmed cell death is operated to hamper autoimmunity and damage to normal cells. Only a few CD8+ T cells (5%–10%) survive to continue as long-term memory T cells. They are categorized into central memory T cells (which are CD45RA– CCR7+) circulated in lymphoid tissues and effector memory T cells (which are CD45RA–CCR7–) circulated in peripheral tissues such as spleen. ⁴² Memory T cells show more rapid and robust immune responses against tumor cells than what do naïve T cells. Memory cells inhibit tumor cells from growth and metastasis; hence, induction of memory is an ambition of cancer immunotherapy. ²¹

γδ T Lymphocytes

The other type of T cells is γδ T cell, which contains a semi-invariant γδ TCR. They could destroy tumor cells from both hematological and solid tumors following recognition of stress ligands or tumor-derived phosphoantigens. They also produce TNF, and IFN-γ, which play an important role in tumor immunology. ²⁷

Natural Killer T Cells

NK T cells share antigens of both NK cell, CD161, and an invariant CD1d restricted TCR. These cells produce IFNγ and IL-4 to exert an indirect role in immunity against tumor. They also show cytotoxic effects by releasing cytotoxic agents, including perforin, granzyme B, and Fas ligand (FasL). ⁴³

Natural Killer Cells

NK cells are powerful cells of the innate immunity, which employ perforin and granzymes to destroy abnormal cells such as tumor cells. NK cells, which have activating and inhibitory receptors, recognize stress ligands on the tumor cells marked by lack of or decreased MHC molecules. ²⁷,⁴⁴

Inhibitory Immune Cells

Tolerogenic DCs

Based on lower expression of MHC and costimulatory molecules on the surface of immature DCs, tolerogenic DCs are unable to induce an immune response as powerful as mature DCs. They also are not capable of producing proinflammatory cytokines. These immature DCs form tolerogenic response either through removing antigen-specific T cells or through development of Tregs. They also secrete inhibitory cytokines such as IL-10, which hampers secretion of proinflammatory cytokines and debilitates NK cells and T cells, as well as TGF-β, which is necessary for induction and survival of Tregs. ⁴⁵,⁴⁶ Tolerogenic DCs might also be matured DCs, i.e., containing costimulatory molecules on their surface, but that can induce Tregs. ⁴⁷

Alternatively Activated Macrophages (M2s)

Alternatively activated macrophages (M2s) originate from monocytes developed under the effect of inhibitory cytokines such as IL-4, IL-13, IL-10, and TGF-β. M2s exert their inhibitory functions through