Cancers develop secondary to genetic and epigenetic changes that provide the cell with a survival advantage that promotes cellular immortality. Malignancy arises when tumors use mechanisms to evade detection and destruction by the immune system. Many malignancies seem to elicit an immune response, yet somehow manage to avoid destruction by the cells of the immune system. Cancers may evade this immune response by numerous mechanisms. Several targeted immune therapies are available that block some of these inhibitory signals and enhance the cell-mediated immune response. Many of these agents hold significant promise for future treatment of sinonasal and ventral skull base malignancies.
Key points
- •
Malignancy arises when cancer cells evade detection and destruction by immune system cells. The cell-mediated immune response, particularly that involving CD8 + cytotoxic T lymphocytes, is a critical component of the antitumor response.
- •
Activation of the cell-mediated immune response is a complex process involving interactions between tumors and the immune system. This process involves foreign proteins expressed and/or shed by cancer cells (tumor antigens), APCs (including dendritic cells and macrophages), CD4 + helper T lymphocytes, and CD8 + cytotoxic T lymphocytes.
- •
Cancers evade the immune response by numerous mechanisms, including expression of inhibitory immune checkpoint proteins, release of cytokines, and interactions with inhibitory cells in the tumor microenvironment.
- •
Cancers may prevent their own destruction through the exploitation of several inhibitory pathways found on T lymphocytes, including the CTLA-4 and PD-1 pathways. These inhibitory cell-surface interactions between cancer cells, APCs, and lymphocytes are an important therapeutic target.
- •
Several targeted immune therapies that block these inhibitory interactions have resulted in unprecedented clinical efficacy in the treatment of numerous malignancies and may present a novel therapeutic approach to the treatment of sinonasal and ventral skull base malignancies.
Introduction
The notion that the immune system is important in defending against malignancy had first been postulated more than 100 years ago by Robert Ehrlich, who suggested that cancer would occur with high frequency if not for host immune defense preventing tumor growth. Cancers arise secondary to genetic and epigenetic changes that provide the cell with a survival advantage that promotes cellular immortality. Cells that undergo these changes often express foreign antigens on their surface that would ordinarily be expected to stimulate a host immune response to destroy them. Malignancy arises when tumors use mechanisms to evade detection and destruction by the immune system.
Following the discovery of T cells in the 1940s came the concept of “immunosurveillance,” the process by which the immune system is able to identify and destroy transformed cells to prevent formation of neoplastic disease. For several decades, scientists have worked to find ways to harness the power of the host’s own immune system in the fight against cancer. Many malignancies seem to elicit an immune response, yet somehow manage to avoid destruction by the cells of the immune system. For example, several studies have shown that large subsets of head and neck squamous cell carcinomas (HNSCCs) demonstrate the presence of CD8 + cytotoxic T lymphocytes and that their presence may be associated with improved response to chemotherapy. Because these tumor-infiltrating lymphocytes function in the immune system to destroy abnormal cells, the question arises: how did these cancers avoid destruction by the host immune system? Furthermore, is there a way to exploit this immune response and make it reactive to the malignant cells?
In recent years there have been unprecedented advances in targeted cancer immunotherapy that are dramatically improving outcomes for several different malignancies, including advanced metastatic cancers that previously had minimal hope for long-term survival. This article discusses some of these remarkable clinical findings and explores their potential for use in treatment of various sinonasal and ventral skull base malignancies.
Immunology Basics
To understand the role of the immune system in the development of malignancy and the mechanisms by which tumors evade the immune system, it is important to understand some essential principles of immunology. Broadly, the immune system is divided into innate and adaptive components ( Tables 1 and 2 ).
| Components of Innate Immunity | Function |
|---|---|
| Epithelial cells | Act as barrier to infection |
| Complement proteins | Circulating proteins that can induce a variety of inflammatory response to pathogens |
| Select Cells of Innate Immunity | Function |
|---|---|
| Monocytes | May differentiated into macrophages or monocytes in response to infection, neoplastic disease, or inflammation |
| Macrophages | Migrates from blood vessels into tissues, consumption of pathogens and cancerous cells by phagocytosis, may present antigens to activate the adaptive immune response |
| Dendritic cell | Presents antigens on its surface resulting in activation of the adaptive immune response |
| Neutrophils | Represent 50%–60% of circulating leukocytes, release products to kill pathogens, stimulate immune response |
| Natural killer cell | Possess cell-killing ability, can destroy tumor cells and cells infected with viruses |
| Types of Lymphocytes | Function |
|---|---|
| B lymphocyte | Production of antibodies, neutralization of microbes, facilitates phagocytosis |
| Helper CD4 + T lymphocyte | Activates a variety of other cell types (B lymphocytes, other T lymphocytes, including cytotoxic T lymphocytes, macrophages) and mediates inflammatory response |
| Cytotoxic CD8 + T lymphocyte | Kills infected or neoplastic cells |
| Regulatory T lymphocytes (regulatory T cells) | This is a subset of CD4 + lymphocytes that inhibits the immune response |
Innate Immunity
Innate immunity refers to an always-present system that can immediately defend against the development of infections and neoplasia. The components of innate immunity include epithelial cells that act as a barrier to infection; complement proteins; and a variety of cell types, such as monocytes, macrophages, dendritic cells, natural killer cells, eosinophils, mast cells, and basophils. Some of these pertinent components are described in more detail in Table 1 .
Adaptive Immunity
Adaptive immunity specifically refers to lymphocytes and their products, such as antibodies. This powerful component of the immunity system is not immediately available to defend against pathologic states, but requires additional steps to become active. This includes presentation of a foreign antigen to B or T lymphocytes by antigen presenting cells (APCs), such as dendritic cells and macrophages. After antigen presentation, differentiation and proliferation of lymphocytes results in a specific response to the presented pathology, including infection or the presence of neoplastic cells. Adaptive immunity is separated into two unique types of responses: humoral and cell-mediated (see Table 2 ). Humoral immunity specifically refers to B lymphocytes and the antibodies that they produce. Cell-mediated immunity refers to immunity that is mediated by the many types of T lymphocytes with several different effector functions (see Table 2 ). Cell-mediated immunity is critical to the detection and destruction of malignant cells.
The Immune System and Malignancy
Activation of the adaptive immune response, particularly cell-mediated immunity, is crucial to the body’s response to malignancy. Before discussing mechanisms by which cancer cells are able to evade the immune system, we explain how the cell-mediated response becomes activated in the presence of malignancy.
Cancer cells express many different proteins that are recognized as foreign by the immune system. This includes abnormally expressed protein products, oncogenes, mutated tumor-suppressor proteins, and viral antigens that are expressed by virally transformed cancerous cells. Most of these protein products are expressed as part of the class I major histocompatibility complex (MHC) that is found on the cellular surface. When proteins are expressed in association with MHC molecules on the cell surface, they are referred to as antigens. APCs can detect these antigens and present them to T lymphocytes found within lymph nodes to activate the cell-mediated immune response. Following antigen presentation, these antigens are recognized on tumor cells by CD8 + cytotoxic T lymphocytes, which enter the circulation and migrate to the site of the antigen to carry out their effector function and destroy the abnormal cell.
A key method of destroying cancer cells by the immune system relies on the activation of CD8 + cytotoxic T lymphocytes. The process of activating CD8 + cytotoxic T lymphocytes is mediated by APCs and also by CD4 + helper T lymphocytes. A variety of cell types act as APCs, including dendritic cells and macrophages. APCs consume antigens that are produced by the tumor and then present them to T lymphocytes to activate them. The combination of APCs and/or CD4 + helper T-lymphocyte interactions then contributes to the activation of CD8 + cytotoxic T lymphocytes that may migrate to tumor tissues and carry out their effector function: destruction of malignant cells ( Fig. 1 ).
Activation of T lymphocytes depends on a two-signal process: interaction between the T-cell receptor and an MHC molecule on an APC; and interaction between costimulatory proteins found on APCs, CD4 + T lymphocytes, and/or the cancer cells ( Fig. 2 ). The first required signal that a T lymphocyte must receive to become active corresponds to the interaction between the T-cell receptor and an MHC molecule that is presenting a peptide antigen on the cell surface of an APC or tumor cell. The second signal corresponds to costimulation, that is, positive signaling by receptors found on the surface of the T lymphocyte and the APC or cancer cell. Many cells of the body express inhibitory proteins, such as B7 and programmed death ligand 1 (PD-L1), which interact with “checkpoint” receptors on the T cell (cytotoxic T-lymphocyte-associated protein [CTLA]-4 and programmed death [PD]-1). These inhibitory interactions compete with the stimulatory “signal 2” required for activation of the T lymphocyte and can inhibit the cell-mediated immune response. Cancer cells may exploit this inhibitory feature of T lymphocytes and often express these inhibitory proteins (PD-L1, B7) as a mechanism by which they are able to evade attack by the immune system. The balance between required stimulatory signals (eg, CD28/B7 interactions) and inhibitory signals (eg, CTLA-4/B7, PD-1/PD-L1, or PD-L2) determines whether a T cell becomes active ( Fig. 3 ).
Introduction
The notion that the immune system is important in defending against malignancy had first been postulated more than 100 years ago by Robert Ehrlich, who suggested that cancer would occur with high frequency if not for host immune defense preventing tumor growth. Cancers arise secondary to genetic and epigenetic changes that provide the cell with a survival advantage that promotes cellular immortality. Cells that undergo these changes often express foreign antigens on their surface that would ordinarily be expected to stimulate a host immune response to destroy them. Malignancy arises when tumors use mechanisms to evade detection and destruction by the immune system.
Following the discovery of T cells in the 1940s came the concept of “immunosurveillance,” the process by which the immune system is able to identify and destroy transformed cells to prevent formation of neoplastic disease. For several decades, scientists have worked to find ways to harness the power of the host’s own immune system in the fight against cancer. Many malignancies seem to elicit an immune response, yet somehow manage to avoid destruction by the cells of the immune system. For example, several studies have shown that large subsets of head and neck squamous cell carcinomas (HNSCCs) demonstrate the presence of CD8 + cytotoxic T lymphocytes and that their presence may be associated with improved response to chemotherapy. Because these tumor-infiltrating lymphocytes function in the immune system to destroy abnormal cells, the question arises: how did these cancers avoid destruction by the host immune system? Furthermore, is there a way to exploit this immune response and make it reactive to the malignant cells?
In recent years there have been unprecedented advances in targeted cancer immunotherapy that are dramatically improving outcomes for several different malignancies, including advanced metastatic cancers that previously had minimal hope for long-term survival. This article discusses some of these remarkable clinical findings and explores their potential for use in treatment of various sinonasal and ventral skull base malignancies.
Immunology Basics
To understand the role of the immune system in the development of malignancy and the mechanisms by which tumors evade the immune system, it is important to understand some essential principles of immunology. Broadly, the immune system is divided into innate and adaptive components ( Tables 1 and 2 ).
| Components of Innate Immunity | Function |
|---|---|
| Epithelial cells | Act as barrier to infection |
| Complement proteins | Circulating proteins that can induce a variety of inflammatory response to pathogens |
| Select Cells of Innate Immunity | Function |
|---|---|
| Monocytes | May differentiated into macrophages or monocytes in response to infection, neoplastic disease, or inflammation |
| Macrophages | Migrates from blood vessels into tissues, consumption of pathogens and cancerous cells by phagocytosis, may present antigens to activate the adaptive immune response |
| Dendritic cell | Presents antigens on its surface resulting in activation of the adaptive immune response |
| Neutrophils | Represent 50%–60% of circulating leukocytes, release products to kill pathogens, stimulate immune response |
| Natural killer cell | Possess cell-killing ability, can destroy tumor cells and cells infected with viruses |
| Types of Lymphocytes | Function |
|---|---|
| B lymphocyte | Production of antibodies, neutralization of microbes, facilitates phagocytosis |
| Helper CD4 + T lymphocyte | Activates a variety of other cell types (B lymphocytes, other T lymphocytes, including cytotoxic T lymphocytes, macrophages) and mediates inflammatory response |
| Cytotoxic CD8 + T lymphocyte | Kills infected or neoplastic cells |
| Regulatory T lymphocytes (regulatory T cells) | This is a subset of CD4 + lymphocytes that inhibits the immune response |
Innate Immunity
Innate immunity refers to an always-present system that can immediately defend against the development of infections and neoplasia. The components of innate immunity include epithelial cells that act as a barrier to infection; complement proteins; and a variety of cell types, such as monocytes, macrophages, dendritic cells, natural killer cells, eosinophils, mast cells, and basophils. Some of these pertinent components are described in more detail in Table 1 .
Adaptive Immunity
Adaptive immunity specifically refers to lymphocytes and their products, such as antibodies. This powerful component of the immunity system is not immediately available to defend against pathologic states, but requires additional steps to become active. This includes presentation of a foreign antigen to B or T lymphocytes by antigen presenting cells (APCs), such as dendritic cells and macrophages. After antigen presentation, differentiation and proliferation of lymphocytes results in a specific response to the presented pathology, including infection or the presence of neoplastic cells. Adaptive immunity is separated into two unique types of responses: humoral and cell-mediated (see Table 2 ). Humoral immunity specifically refers to B lymphocytes and the antibodies that they produce. Cell-mediated immunity refers to immunity that is mediated by the many types of T lymphocytes with several different effector functions (see Table 2 ). Cell-mediated immunity is critical to the detection and destruction of malignant cells.
The Immune System and Malignancy
Activation of the adaptive immune response, particularly cell-mediated immunity, is crucial to the body’s response to malignancy. Before discussing mechanisms by which cancer cells are able to evade the immune system, we explain how the cell-mediated response becomes activated in the presence of malignancy.
Cancer cells express many different proteins that are recognized as foreign by the immune system. This includes abnormally expressed protein products, oncogenes, mutated tumor-suppressor proteins, and viral antigens that are expressed by virally transformed cancerous cells. Most of these protein products are expressed as part of the class I major histocompatibility complex (MHC) that is found on the cellular surface. When proteins are expressed in association with MHC molecules on the cell surface, they are referred to as antigens. APCs can detect these antigens and present them to T lymphocytes found within lymph nodes to activate the cell-mediated immune response. Following antigen presentation, these antigens are recognized on tumor cells by CD8 + cytotoxic T lymphocytes, which enter the circulation and migrate to the site of the antigen to carry out their effector function and destroy the abnormal cell.
A key method of destroying cancer cells by the immune system relies on the activation of CD8 + cytotoxic T lymphocytes. The process of activating CD8 + cytotoxic T lymphocytes is mediated by APCs and also by CD4 + helper T lymphocytes. A variety of cell types act as APCs, including dendritic cells and macrophages. APCs consume antigens that are produced by the tumor and then present them to T lymphocytes to activate them. The combination of APCs and/or CD4 + helper T-lymphocyte interactions then contributes to the activation of CD8 + cytotoxic T lymphocytes that may migrate to tumor tissues and carry out their effector function: destruction of malignant cells ( Fig. 1 ).
