**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 [7–10]. These checkpoints can be targeted to enhance phagocytic activity and increase the efficiency of immune surveillance. Additionally, the development of neo-antigenbased cancer vaccines that utilize the phagocytic characteristics of dendritic cells has provided new avenues for cancer treatment [11–14].

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.

### **2. Phagocytosis of cancer cells**

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 [15–19].

### **3. Anti-body dependent cellular phagocytosis (ADCP)**

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 *Harnessing Phagocytosis for Cancer Treatment DOI: http://dx.doi.org/10.5772/intechopen.110619*

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].

#### **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 [46–48].


#### **Table 1.**

*lists some examples of clinically used monoclonal antibodies that utilize ADCP to treat cancers.*

#### **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.*

#### **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].
