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Phagocytosis is a critical component of the body’s immune response, essential for preventing and controlling infections and defending against cancer cells. Macrophages and dendritic cells are the primary immune cells responsible for phagocytosis, recognizing and engulfing abnormal cells, including cancer cells. Although phagocytosis can prevent the spread of cancer cells by destroying them in a healthy immune system, cancer cells may evade this immune mechanism and form tumors. As an emerging therapeutic strategy, boosting phagocytosis is being utilized to target and eliminate cancer cells. This chapter provides an overview of the role of phagocytosis in cancer prevention and progression, highlighting its significance in the body’s immune response to cancer. Furthermore, it explores various strategies and approaches to harness the power of phagocytosis in the fight against cancer.
Department of Molecular, Cell and Cancer Biology, UMass Chan Medical School, Worcester, USA
*Address all correspondence to: alok.mishra@umassmed.edu
1. Introduction
In the 1880s, Elie Metchnikoff, who studied marine invertebrates, observed special cells that were capable of attacking tiny thorns in starfish larvae. This was his first discovery of phagocytosis. For his pioneering work in cellular immunity, he was awarded the Nobel Prize alongside Paul Ehrlich in 1908 [1].
Phagocytosis is basically referred to as the ingestion of food particles by unicellular organisms, but in multicellular organisms, it is a specialized process carried out by phagocytes, which are a set of specialized cells. The examples of phagocytes in vertebrates include neutrophils, macrophages, monocytes, dendritic cells, osteoclasts, and eosinophils [2].
In the context of cancer, phagocytosis plays a crucial role in the body’s defense against malignant cells. Normally, phagocytic cells, such as macrophages are responsible for recognizing and engulfing cancer cells, thereby preventing their spread and growth. However, in some cases, cancer cells can evade the immune system by modifying their surface antigens or secreting cytokines that suppress the recognition ability and activity of phagocytic cells [3, 4].
Macrophages and dendritic cells are the two key components of the innate immune system that play a crucial roles in defending the human body against emerging threats. These cells not only help in eliminating newly transformed cells, but also play a vital role in activating the adaptive immune system when needed. Despite their important role in immune surveillance, there is growing evidence that the polarization of these phagocytes by tumor-derived factors can lead to a pro-tumorigenic response [5, 6].
The recent discoveries of phagocytic immune checkpoints, such as CD47, LILRB1/2, CD24 and PDL-1, has revitalized the field of phagocytosis research [7, 8, 9, 10]. These checkpoints can be targeted to enhance phagocytic activity and increase the efficiency of immune surveillance. Additionally, the development of neo-antigen-based cancer vaccines that utilize the phagocytic characteristics of dendritic cells has provided new avenues for cancer treatment [11, 12, 13, 14].
In this chapter, I will provide an overview of phagocytic process and its role in tumor biology as well as present the fundamental concepts of this field of research. I will also examine how phagocytes can be harnessed as a tool for cancer therapy and the potential of utilizing these cells in combination with other treatments to achieve improved outcomes.
Cellular phagocytosis is a complex process that involves the recognition and engulfment of target cells, including cancer cells, by specialized cells known as phagocytes. Phagocytes such as macrophages and dendritic cells are equipped with surface receptors that can recognize pro-phagocytic signals or “eat me” signals on the surface of the target cells. For example, the presentation of calreticulin (CALR) on the surface of cancer cells is one such signal that helps macrophages and dendritic cells to recognize and initiate the phagocytic process.
The process of phagocytosis of cancer cells can be broken down into five main steps: recognition, activation, engulfment, digestion, and elimination. In the recognition step, phagocytes identify and bind to the target cells, leading to the activation of the phagocyte. In the activation step, the phagocyte is stimulated to engulf the target cell, leading to its internalization. The engulfment step is followed by the digestion of the target cell, in which it is broken down and degraded within the phagocyte. Finally, the elimination step involves the removal of the digested material from the phagocyte, which may occur through exocytosis.
In addition to phagocytosis, both macrophages and dendritic cells play an important role in activating the adaptive immune response against cancer cells. These cells can present antigens from cancer cells to T cells, which are responsible for recognizing and eliminating cancer cells in a specific manner. This process is crucial for effective anti-cancer immune responses, and its failure can contribute to cancer progression and the development of immune evasion mechanisms [15, 16, 17, 18, 19].
The process of phagocytsis is also facilitated by anti-bodies formed against the surface antigen. This form of phagocytosis is called anti-body dependedent cellular phagocytosis or ADCP.
ADCP allows immune cells, such as macrophages and dendritic cells, to recognize and engulf cancer cells. This is achieved through the binding of specific antibodies to the cancer cells, creating a bridge that enables the immune cells to phagocytose the cancer cells. These antibodies can either be naturally produced by the body or artificially engineered to target cancer cells.
Fcγ receptors play a crucial role in cancer cell phagocytosis by antibody-dependent cell phagocytosis (ADCP). These receptors are present on the surface of macrophages and other immune cells and recognize the constant region (Fc region) of antibodies bound to antigens on the surface of cancer cells. This recognition event triggers the phagocytosis of the cancer cell by the immune cells [20, 21].
ADCP plays a crucial role in the body’s natural defense mechanism against cancer and is a key component of some immunotherapies used for cancer treatment. For instance, monoclonal antibody therapy utilizes engineered antibodies that target specific cancer cells and trigger ADCP, leading to the destruction of the cancer cells by immune cells (Table 1) [20, 21, 43, 44].
lists some examples of clinically used monoclonal antibodies that utilize ADCP to treat cancers.
3.1 Anti-CD20 (Rituximab)
Rituximab, also known as Anti-CD20, is a monoclonal antibody targeting the CD20 antigen expressed on the surface of malignant B-cells. CD20 is a transmembrane glycoprotein found on the surface of pre-B and mature B-lymphocytes and is used as a therapeutic target for the treatment of B-cell malignancies such as non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL) [23, 45].
Rituximab works by binding to the CD20 antigen on the surface of cancer cells, leading to antibody-dependent cellular phagocytosis (ADCP) and subsequent destruction of the cancer cells by immune cells. ADCP is a mechanism in which immune cells, such as macrophages and dendritic cells, are able to recognize and engulf cancer cells through the binding of antibodies to the cancer cells [46, 47, 48].
3.2 Anti-HER2 (Trastuzumab)
Trastuzumab is a monoclonal antibody targeting the human epidermal growth factor receptor 2 (HER2) protein. This protein is overexpressed in some breast cancers and is associated with an aggressive form of the disease. Trastuzumab works by binding to HER2 on the surface of cancer cells, leading to antibody-dependent cellular phagocytosis (ADCP). This process signals immune cells to engulf and destroy the cancer cells [49].
Trastuzumab has been shown to improve response rates and survival outcomes in patients with HER2-positive breast cancer [25, 26]. It is often used in combination with chemotherapy (e.g. paclitaxel, doxorubicin) and/or radiation therapy. Studies have demonstrated its clinical efficacy, such as the “HERA” trial which showed improved disease-free survival in HER2-positive breast cancer patients receiving Trastuzumab and chemotherapy (Figure 1) [50].
Figure 1.
(A) Steps involves in phagocytosis mediated killing of cancer cells, and (B) antibody-dependent cellular phagocytosis. (ADCP); Monoclonal antibodies (mAbs) (e.g., Rituximab) can bind to both macrophages and tumor cells, leading to the formation of a complex that triggers ADCP. As a result, macrophages engulf the tumor cells that are opsonized by antibodies. The figure was created using BioRender.com.
4. Mechanism of evasion of cellular phagocytosis by cancer cells
Phagocytosis plays a vital role in preventing the spread and growth of cancer cells by eliminating them. However, cancer cells can often evade the immune system, reducing the effectiveness of phagocytosis. They empoly several molecular and cellular mechanisms to evade phagocytosis mediated killing by phagocytes [51, 52, 53, 54, 55, 56].
Modifying surface antigens: Cancer cells can modify their surface antigens to evade recognition by phagocytic cells. This can include changes to proteins, lipids, or carbohydrates on the cell surface.
Suppressing phagocytic activity: Cancer cells can secrete cytokines and chemokines that suppress the activity of phagocytic cells. This can reduce the efficiency of phagocytosis and allow cancer cells to proliferate.
Inducing immune tolerance: Cancer cells can induce immune tolerance by producing molecules that activate regulatory T cells, which suppress the immune response. This can reduce the phagocytic activity of immune cells and allow cancer cells to evade destruction.
Hiding in immune privileged sites: Some cancer cells can hide in immune privileged sites, such as the central nervous system or the eye, where they are protected from the immune response and phagocytosis.
Expressiong phagocytic checkpoints: Cancer cells can also stimulate a phagocytosis-resistant phenotype by altering the expression of surface proteins and other molecular markers that can acts as immune checkpoint. These immune checkpoint are popularly known as “Do not eat me signal” these signals can make the cancer cells less recognizable to phagocytic cells and reduce the efficiency of phagocytosis. Following are the known immune checkpoints axes that have been extensively studies and targeted for cancer tratement.
4.1 The immune checkpoints and inhibitors
Immune checkpoints help regulate immune responses and prevent overactive immune responses.
One type of immunotherapy is checkpoint inhibition, which targets immune checkpoint molecules to release the brakes on the immune system and enhance its ability to attack cancer cells. ICIs have shown promising results in preclinical studies and is being actively investigated as a potential treatment for cancer.
Checkpoint inhibition is currently a highly active area of research in the field of cancer treatment, with the aim of developing effective immunotherapies that can help improve patient outcomes and provide new treatment options for cancer patients. Following are some examples of the phagocytic immune checkpoint axes that has been targeted to treat various types of cancers.
4.2 CD47- SIRPα
CD47 is a protein that can be found on the surface of various cells, including cancer cells. Its primary function is to act as a “do not eat me” signal that prevents phagocytosis, the process by which phagocytic cells destroy other cells. This is achieved by CD47 interacting with its receptor, SIRPα, which inhibits the activation of phagocytic pathways, ultimately blocking phagocytosis. The CD47-SIRPα interaction is a crucial component of immune tolerance, helping to differentiate between self and non-self and prevent the destruction of healthy cells. Despite its role in immune tolerance, researchers are investigating the potential for using the CD47-SIRPα interaction as a strategy for cancer therapy. By blocking this interaction, the phagocytic ability of the immune system can be enhanced, which may lead to increased removal of cancer cells. This can be achieved through the use of anti-CD47 monoclonal antibodies or small molecule inhibitors of the CD47-SIRPα interaction, such as Hu5F9-G4 or Sen177. This approach has promising potential as a cancer therapy strategy (Table 2) [14, 45, 56, 62, 63, 64, 65, 66].
Inhibitor
Type
Target
Mechanism of action
Clinical status
Cancer types being studied
Ref.
Hu5F9-G4 (5F9)
Monoclonal antibody
CD47
Blocks CD47-SIRPα interaction, promoting phagocytosis of cancer cells
Some examples of immune check point inhibitors that induces cellular phagocytosis.
4.3 CD24-SIGLEC10
CD24 and SIGLEC10 are cell surface markers expressed on immune cells. CD24 is primarily expressed on certain B cells and SIGLEC10 is expressed on immune cells called macrophages and myeloid-derived suppressor cells. Both CD24 and SIGLEC10 have been shown to act as immune checkpoint molecules, meaning they help regulate immune responses and prevent overactive immune responses.
Targeting CD24 and SIGLEC10 with immunotherapies has shown promising results in preclinical studies and is being actively investigated as a potential treatment for cancer [8, 9].
4.4 LILRB1/2
LILRB1 and LILRB2 are members of the leukocyte immunoglobulin-like receptor (LILR) family of receptors and are expressed on phagocytic cells such as macrophages, dendritic cells, and monocytes. These receptors serve as phagocytic checkpoints by regulating the phagocytic activity of these immune cells and modulating their ability to engulf and degrade pathogens and cellular debris. LILRB1 and LILRB2 can also regulate the immune response by modulating the activation and function of T cells and natural killer cells. In this way, they play a crucial role in maintaining immune homeostasis and preventing overactive immune responses. Studies have shown that LILRB1 and LILRB2 can also be exploited by cancer cells to evade the immune system and persist in the body. In light of these findings, the targeting of these receptors as phagocytic checkpoints has gained attention as a promising strategy in cancer immunotherapy. Inhibiting the activity of LILRB1 and LILRB2 has been shown to enhance the phagocytic activity of immune cells and improve their ability to target and clear cancer cells. This has led to ongoing research in the field of cancer immunotherapy to further explore the potential of targeting these receptors as phagocytic checkpoints [14, 67, 68].
4.5 PDL-1-PD1
PD-1 (programmed cell death protein 1) and its ligand PD-L1 (programmed cell death ligand 1) are proteins that are involved in regulating the immune response. They are known as immune checkpoint molecules because they prevent the immune system from overreacting and attacking healthy tissues. Traditionally, PD-1/PD-L1 has been viewed as a T cell immune checkpoint, where PD-1 on the surface of T cells interacts with PD-L1 on the surface of other cells, including cancer cells and antigen-presenting cells. This interaction leads to the inhibition of T cell activity, which prevents the immune system from attacking healthy tissues and can allow cancer cells to evade the immune system. However, recent research has also shown that PD-1/PD-L1 is involved in regulating phagocytosis. PD-L1 can be expressed on the surface of tumor cells and other cells, and when it interacts with PD-1 on the surface of phagocytes, it inhibits their ability to perform phagocytosis. This means that by blocking the interaction between PD-1 and PD-L1, it may be possible to enhance the ability of phagocytes to remove foreign particles and to enhance the immune response against cancer cells. As a result, there is growing interest in the development of drugs that target PD-1/PD-L1 for the treatment of cancers [18, 69].
Small molecule activators of macrophages offer a potential alternative to traditional cancer treatments, such as chemotherapy and radiation therapy, and may also be used in combination with other cancer treatments for a more comprehensive approach to cancer therapy. The goal of using small molecule activators is to enhance the natural ability of macrophages to recognize and eliminate cancer cells, potentially leading to cancer elimination. This type of therapy is still in the early stages of development, but has shown promising results in preclinical studies and early clinical trials.
Some examples of small molecule activators of macrophages include:
CSF-1R inhibitors: These are drugs that target the colony-stimulating factor 1 receptor (CSF-1R), a protein that regulates the growth and survival of macrophages. By inhibiting CSF-1R, these drugs can deplete the pro-tumerogenic tumor associated macrophages or repolarize them to anti-tumerigeneic thereby, enhancing their ability to phagocytize cancer cells (e.g. Emactuzumab, Pexidartinib) [70, 71].
Toll-like receptor (TLR) agonists: TLRs are proteins found on the surface of immune cells that help to detect and respond to pathogens. TLR agonists are drugs that mimic the action of pathogens and activate TLRs, leading to increased activation and phagocytic capacity of macrophages (e.g., IMO-2125) [72, 73, 74].
5.1 Cell-based therapies
Phagocyte-based cell therapies are a type of cancer treatment that leverage the phagocytic properties of immune cells to eliminate cancer cells. One example of such a therapy is dendritic cell (DC) vaccines, which involve extracting dendritic cells from the patient’s blood, enriching them with tumor-associated antigens, and then reintroducing them into the patient. The enriched DCs then travel to the lymph nodes, where they display the antigens to T-cells, eliciting an immune response against the cancer cells [75, 76, 77].
Additionally, researchers have developed enginnered macrophages and CAR (chimeric antigen receptor) macrophages as alternative forms of phagocyte-based cell therapy to combat cancer [78, 79].
5.2 Dendritic cells based cancer vaccines
Dendritic cells (DCs) are specialized antigen-presenting cells that originate from bone marrow progenitors. They can take up and process antigens through various mechanisms such as phagocytosis, receptor-mediated endocytosis, or micropinocytosis, depending on the type of antigen and their activation status. DCs can recognize antigens associated with pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). These processed antigens are presented on the surface of DCs by MHC I or MHC II molecules to CD4+ or CD8 + T-cells, respectively (Figure 2).
Figure 2.
Illustration of dendritic cell maturation and antigen presentation to T cells. Figure downloaded from Biorender.com(on 02.15.2023).
DCs can activate various immune cells including naïve and memory T-cells, natural killer (NK) cells, and natural killer T (NKT) cells, making DC vaccines a promising approach for cancer immunotherapy. Recent clinical trials have shown that tumor-antigen-preloaded DCs can initiate anti-tumor immune responses in patients, indicating the potential of DCs in cancer therapy.
The production of a DC vaccine involves several steps. First, tumor cells are obtained during surgical resection of the patient’s tumor. These tumor cells contain specific antigens that are unique to that patient’s tumor.
Next, the patient’s peripheral blood monocytes are obtained through a process called leukapheresis. These monocytes are then differentiated ex vivo (outside the body) into dendritic cells, which are antigen-presenting cells that can activate the immune system’s T-cells. The dendritic cells are then “trained” to recognize the patient’s tumor cells. This is done by ex vivo pulsing the dendritic cells with tumor lysate or peptides derived from the patient’s own tumor cells.
After the dendritic cells are trained, they are injected back into the patient. The injected DC-vaccine enables the dendritic cells to present the tumor antigens to the patient’s CD4 and CD8 T-cells, which are part of the adaptive immune system. The T-cells then become activated a exerts highly specific immune response against the patient’s tumor cells. This specific immune response can lead to the killing of the tumor cells, as well as the prevention of further tumor growth (Figure 3).
Figure 3.
Illustrates the mechanism of action of a DC vaccine in the body. The vaccine involves the ex vivo maturation and loading of dendritic cells with tumor-associated antigens (TAA). Once the vaccine is administered, the activated T cells that are specific to the TAA circulate throughout the body, searching for cancer cells that express the same antigen. Upon encountering a cancer cell, the T cells attach to it and unleash their cytotoxic activity. The figure was created using BioRender.com.
The aim of these vaccines is to activate the patient’s immune system against the cancer cells, with the hope of inducing remission or eradication of the cancer. Although still in the early stages of development, dendritic cell-based cancer vaccines have shown promising results in clinical trials, particularly when combined with other immunotherapy treatments (Figure 3) [80, 81, 82].
Follwing are some examples of dendritic cell-based cancer vaccines.
PROSTVAC-V/F: This vaccine is based on a virus that has been engineered to produce prostate-specific antigens (PSAs). The vaccine is designed to stimulate an immune response against prostate cancer cells that express PSAs [83].
DCVAC/PCa: This vaccine is based on dendritic cells that have been exposed to antigens from prostate cancer cells. The vaccine is designed to stimulate an immune response against prostate cancer cells [84].
DCVax-L: The experimental vaccine therapy known as DCVax®-L is created using dendritic cells that are loaded with cell extracts or lysates from the cancer cells of the patient. Its purpose is to trigger the patient’s immune system to generate a response against the particular cancer cells of the patient. This treatment is intended for brain tumor patients (NCT00045968) [85].
5.3 CAR-macrophages
CAR (Chimeric Antigen Receptor) macrophages are a type of genetically modified macrophages that have been engineered to enhance their phagocytic ability. CAR macrophages are created by introducing a CAR gene into the macrophages, which codes for a chimeric antigen receptor. This CAR allows the macrophages to specifically target and phagocytize specific cells, such as cancer cells, by recognizing specific antigens present on their surface [79]. The goal of this technology is to create a new way to fight cancer and other diseases by harnessing the natural abilities of macrophages to engulf and destroy unwanted cells.
CAR-M therapies have demonstrated the ability to eliminate tumor cells both in vitro and in preclinical in vivo models. In vitro, human CAR-M have been shown to exhibit antigen-specific phagocytosis, as well as secretion of cytokines/chemokines and the ability to kill target antigens [79]. In two immunodeficient NSG xenograft models, a single dose of anti-HER2 CAR-M significantly reduced the burden of tumors and prolonged overall survival against HER2+ SKOV3 tumors. Additionally, CAR-M that were administered intravenously (IV) were found to localize to tumors in several xenograft models and persisted in tumor-free mice (primarily within the liver) for at least 62 days, as detected by whole-body bioluminescent imaging. In vitro analysis further demonstrated that CAR-M were capable of coordinating an antitumor T cell response by recruiting T cells and cross-presenting antigens from phagocytosed cells [19, 86, 87].
5.4 Using nanoparticles to promote phagocytosis
Another way to potentially enhance the phagocytic response is through the use of nanoparticles. Nanoparticles have been extensively studied for their ability to induce macrophage polarization states, as different types of nanoparticles can influence macrophage polarization toward either a pro-inflammatory (M1) or anti-inflammatory (M2) phenotype. When tumor-associated macrophages (TAMs) recognize nanoparticles as foreign, they will engulf them via phagocytosis, releasing the contents of the nanoparticle within the TAMs. Therefore, nanoparticles can be loaded with drugs or contents designed to induce macrophage polarization toward a more phagocytic phenotype, reprogramming them with an affinity for phagocytosis. This makes nanoparticles a potentially attractive vehicle for delivering therapeutic agents that can boost the immune response against cancer [88, 89].
Additionally, recent studies have shown that nanoparticles can be designed to not only enhance the phagocytic response, but also to help stimulate an anti-tumor T cell response by recruiting T cells and cross-presenting antigens from phagocytosed cells. This highlights the potential for nanoparticles to be used in combination with other immunotherapies, such as CAR-T cells or checkpoint inhibitors, to further enhance the immune response against cancer [55, 88, 89].
Macrophages and dendritic cells play a crucial role in preventing the growth of cancer cells by recognizing, engulfing, digesting, and eliminating them through phagocytosis. This process is a key aspect of the body’s defense against cancer, but cancer cells can develop various mechanisms to evade immune-mediated killing. Understanding these immune evasion mechanisms is important for developing strategies to improve phagocytic activity in cancer patients and enhance the effectiveness of cancer treatments. In recent years, there has been growing interest in using immune checkpoint inhibitors and engineered cell-based immunotherapies to enhance phagocytic activity in cancer patients. In conclusion, phagocytosis is an important cellular process in the body’s defense against cancer, and it plays a crucial role in the development of immunotherapies for the treatment of cancer. Overall, this chapter underscores the importance of phagocytosis in cancer prevention and treatment, and highlights the potential for using this process to develop novel and effective cancer therapies.
I acknowledge Late Prof. Michael Green, and the Department of Molecular Cell and Cancer Biology, UMass Chan Medical School, for providing all the necessary resources and support.
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Written By
Alok K. Mishra
Submitted: 17 February 2023Reviewed: 20 February 2023Published: 20 April 2023
Open access peer-reviewed chapter
