Immune response to cancer

Also known as: T-cell or cellular immune response, B-cell or humoral immune response

Definition: The body’s immune response to cancer, in which tumor cells are recognized and killed, relies on T cells (the cellular immune response) and B cells (the humoral immune response). T cells are a type of lymphocyte, or white blood cell, that matures in the thymus gland in the neck, and B cells are lymphocytes produced in the bone marrow. To escape immune-mediated cell death, tumor cells use several strategies. However, because of the potential benefits of generating tumor-specific immunity, tumor immunotherapy is being studied as a treatment for cancer.

Tumor-associated antigens: T cells and B cells recognize specific proteins, known as antigens, expressed on tumor cells. These immune cells can then become activated and develop antigen-specific immune responses that kill cells expressing these antigens.

There are many types of tumor-associated antigens. They may be reactivated embryonic gene products that are generally not found in normal adult cells but are turned on in some types of tumors, such as the melanoma-associated antigen (MAGE) proteins expressed in melanoma, breast, esophageal, and gastric cancers. Viral gene products are another category, which includes components of the Epstein-Barr virus and the human papillomavirus (HPV) present in nasopharyngeal and cervical cancers, respectively. Tumor antigens may also be mutated, overexpressed, or dysregulated self-proteins. Commonly mutated self-proteins include KRAS and beta-catenin, both found in multiple tumor types. Examples of overexpressed and dysregulated self-proteins include prostate-specific antigen, expressed in prostate cancers, and HER2/neu, expressed in breast, ovarian, and colorectal cancers. By mutating or overexpressing proteins involved in cell cycle regulation and growth control, tumors can divide more and survive longer.

Cellular immunity: For a T cell to become activated, its T-cell receptor (TCR) must recognize antigen fragments, or antigenic peptides, that are bound to the major histocompatibility complex (MHC) expressed on antigen-presenting cells, such as dendritic cells. The interaction of the T-cell receptor and the MHC-peptide complex activates a signal known as signal 1. T cells must also interact with costimulatory molecules on antigen-presenting cells, which produces a signal commonly referred to as signal 2. T cells must receive both signals before they can multiply and carry out their effector functions.

Two major types of T cells are classified by whether they express the CD4 or CD8 protein. T cells expressing the CD4 protein recognize peptides bound to MHC class II. Here, extracellular proteins are taken up by antigen-presenting cells and digested into twelve to twenty amino-acid fragments that associate with MHC class II as it traffics to the cell surface. CD4+ T cells are referred to as helper T cells because they secrete proteins called cytokines that provide survival factors to other immune cells, including various interleukins (IL) and interferon gamma (IFN-γ).

CD8+ T cells recognize peptides bound to MHC class I. Here, intracellular proteins are broken down into eight to ten amino-acid fragments. These fragments are transported into the endoplasmic reticulum via the transporter associated with antigen processing (TAP), loaded onto MHC class I molecules, and exported to the cell surface. CD8+ T cells may also be activated by cross-presentation, in which extracellular antigens released from dying cells are taken up by antigen-presenting cells and associate with MHC class I.

CD8+ T cells are referred to as killer T cells or cytotoxic T lymphocytes. These cells release factors such as perforin and granulysin, which poke holes in the plasma membrane of a target cell and allow water to rush in, ultimately leading to cell death in a process called osmotic lysis. CD8+ T cells also secrete granzyme, a serine protease that can enter target cells and activate caspases, which are enzymes involved in apoptosis (programmed cell death).

Humoral immunity: Whereas T cells recognize peptides bound to MHC molecules, B cells recognize whole or unprocessed antigens on the surface of target cells.

B cells can activate T cells by serving as antigen-processing cells because they express MHC class II. When B cells interact with CD4+ helper T cells, the T cells can activate the B cells and mature them into plasma cells. Plasma cells produce proteins called antibodies, which are specific for certain antigens. Antibodies can bind to antigens on a target cell and cause cell death via the complement pathway, which causes osmotic lysis, and via antibody-dependent cellular cytotoxicity, which recruits natural killer cells that, similar to CD8+ killer T cells, can secrete perforin and granzyme to induce tumor cell death,. Antibodies can also bind to antigens such as growth factor receptors and block their activity.

Immune tolerance: There are mechanisms that control the body’s ability to recognize and respond to foreign (non-self) antigens while not responding to self-antigens. However, since most cancers develop as uncontrolled growths within the body, tumor-associated antigens may be seen as self-proteins. As a result, the immune response to cancer may be limited by immune tolerance.

Central tolerance is a form of immune tolerance that occurs in the thymus or bone marrow during T- or B-cell development and involves the deletion of T or B cells that would respond too well to self-proteins. A similar process of deletion occurs in peripheral tolerance, which takes place outside the thymus or bone marrow, after the T and B cells mature. Other mechanisms of peripheral tolerance include ignorance and anergy. Ignorance occurs when self-reactive T cells are present but not activated by the antigen because the antigen is at low concentrations or not easily accessible to the peripheral blood. T-cell anergy is a state of unresponsiveness and may occur when there is T-cell-receptor ligation (signal 1) in the absence of costimulation (signal 2).

Tumors themselves also have mechanisms to escape immune recognition. They can downregulate antigen-processing factors such as MHC molecules, the TAP transporter, or tumor-specific antigens, which makes it harder for T cells to recognize the antigens on tumor cells. Tumors can also express proteins that provide negative costimulation, leading to reduced T-cell activity or cell death. Some tumors secrete inhibitory cytokines, such as interleukin 10 (IL-10) and tumor growth factor beta (TGF-β), which may inhibit antigen-presenting cells and recruit regulatory T cells. Regulatory T cells account for approximately 5 to 10 percent of CD4+ cells and are characterized by expression of the CD25 protein and the FOXP3 transcription factor. Regulatory T cells can suppress activation of other T cells and have been found to be more prevalent in human cancer patients compared with normal donors.

Therefore, mechanisms of immune tolerance and a tumor’s ability to produce an immunosuppressive environment may limit the activity of the immune cells, allowing cancer to grow within the body.

Immunotherapy: Since T cells and antibodies can specifically target tumor-associated antigens, anticancer therapies that use the immune system may be more specific than traditional cancer therapies such as chemotherapy, which targets all dividing cells, both normal and cancerous. Therefore, tumor immunotherapy may be less toxic and could lead to the development of immunological memory responses.

Tumor vaccines are one type of immune-based therapy, in which tumor cells (or nontumor cells engineered to express tumor antigens) are modified to boost immune responses. These cells can be genetically modified to express MHC molecules or costimulatory molecules and would serve as the antigen-presenting cell to activate T cells. Other types of tumor vaccines use cells that secrete cytokines to recruit and activate the body’s own antigen-presenting cells. Tumor vaccines are being tested in a variety of cancers, including melanoma and breast cancer.

The use of antibodies represents another immune-based platform. For example, rituximab is an antibody specific for the protein CD20, which is expressed on both normal and cancerous B cells, such as those in B-cell non-Hodgkin lymphoma and B-cell leukemia. Depletion of CD20-expressing B cells with rituximab rids the body of cancerous B cells and has been shown to be effective as a first-line therapy and in relapsed cancers. Similarly, HER2/neu is overexpressed in about 30 percent of breast tumors and is associated with a more aggressive cancer. The HER2/neu-specific antibody trastuzumab has been shown to increase survival rates in metastatic breast cancer and reduce relapse rates in early breast cancers.

Tumor immunotherapy represents a different type of cancer treatment and may have benefits over traditional cancer therapies, including higher specificity and better tolerability. In 2010, the US Food and Drug Administration (FDA) approved the first tumor vaccine, sipuleucel-T, which is used for treatment of metastatic prostate cancer that no longer responds to hormone therapy. Sipuleucel-T is created by harvesting antigen-presenting cells from the patient's blood and has been shown to improve overall survival by an average of approximately four months.

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