Does Radiotherapy Affect The Immune System?

Overview

Radiotherapy is the most commonly used standard cancer therapy in those with solid tumours, with up to 60% of cancer patients being irradiated at some point during their treatment.^1,2  Radiotherapy induces DNA damage by concentrating ionising radiation on local tumour cells. This leads to repair by surrounding normal tissue and cell death (apoptosis) in those targeted tumour cells.¹  

Whilst radiotherapy successfully induces anti-tumour immunity,³ little is known about the harmful side effects on the immune system. Radiotherapy can weaken the immune system, particularly if significant amounts of bone marrow, healthy cells, and immune cells are irradiated. These cells have essential roles in immunity. The cells of the immune system, such as lymphocytes (natural killer (NK) cells, T cells, and B cells), macrophages, monocytes, and dendritic cells, are highly radiosensitive. Thus, radiotherapy can lower the number of these immune cells, impairing immunity.⁴ Radiotherapy can also damage the body's lymphatic system, causing an excess accumulation of lymphatic fluid. If the immune system becomes severely damaged, pain and swelling in some body regions may occur, a condition known as lymphedema.⁵  

While the immune system can eliminate tumour cells by pairing innate and adaptive immunity with radiotherapy, some tumour cells may not be destroyed. If some tumours escape into systemic circulation, these cells can create an immunosuppressive environment and grow elsewhere.⁶ Initially, it was believed that the body's natural immune system had no role in radiotherapy-induced tumour responses. Immune cells are radiosensitive, decreasing their levels after radiotherapy.⁷ Similarly, radiotherapy has been shown to impair the mechanisms of monocytes and NK cells in the bone marrow.⁸  

Despite these known side effects, it has recently emerged that the immune system can also be activated by radiotherapy.⁹  Radiotherapy induces cell death and inhibits tumour growth, but can also activate the immune system simultaneously. ⁹  Radiotherapy stimulates the expression of immunomodulatory cells such as antigen-presenting cells, T cells, and stromal cells,¹⁰ making tumour cell antigens more noticeable to the body's immune system for attack.¹¹ 

This article aims to discuss what radiotherapy is, how it affects the body, how the body's immune system reacts to facilitate treatment, and how the immune system is impaired by radiation therapy.

About the Immune System

Blood Cell Types and their Roles 

Immune cells develop from stem cells in the bone marrow and ‘mature’ into different types of white blood cells. Examples of cells involved in immunity, including those that help fight cancer, include:

• Lymphocytes: white blood cells that are made in the bone marrow and circulate in the blood and lymphatic tissue. Lymphocytes include NK cells, T cells, and B cells.
• NK cells: innate immune cells with a cytolytic response to infected or cancer cells.¹²  NK cells have inhibitory receptors on their cell surface that target cancer cells, binding to these cancer cells and programming them for cell death.
• T cells: are cells of the adaptive immune system. They kill infected host cells, activate other immune cells, produce inflammatory markers (cytokines) and regulate immune responses.¹³  CD8 T cells are the most common anti-tumour T cells.¹³  CD8 T cells differentiate into cytotoxic T cells, which produce chemicals such as perforin and granzyme that break down the tumour cells, destroying the target cells.¹⁴ The second type of T cell, CD4 T Helper cells, secrete inflammatory cytokines that promote cytotoxicity of tumour cells and the activity of macrophages and NK cells. This increases the presentation of cancer cell antigens, making them more noticeable for attack.¹⁵  Memory T cells are long-lived cells that mediate faster responses upon repeated encounters with a cancer cell antigen. They protect against infection by the same pathogen.¹³
• B cells: are involved in humoral immunity, which is the process of adaptive immunity induced by the production of antibodies by B cells.¹⁶ Upon activation by an activated helper T cell, B cells clone by mitosis into antibody-secreting plasma cells and memory cells. Plasma cells secrete antibodies that attach to tumour cells and destroy them (primary response). Memory cells circulate in tissues and blood in readiness to respond to future encounters with the same tumour cell. When stimulated, memory cells divide rapidly and develop into plasma cells that produce antibodies (secondary response). ¹³  
• Monocytes are white blood cells that differentiate into macrophages and dendritic cells. They are made in the bone marrow and travel through the blood to tissues and cancerous cells, where they become mature.
• Macrophages: innate immune cells that differentiate from circulating monocytes upon arrival at tissues. Macrophages surround and kill cancerous cells, ingest foreign material, remove tumorous cells undergoing apoptosis, and facilitate immune responses.¹³  
• Innate dendritic cells (DCs): specialised antigen-presenting cells that prime memory T cells and trigger T cell responses.¹³  They prime and consolidate anti-tumour adaptive immune responses; that is, they take up, process, and then present cancerous antigens to adaptive immune cells to mediate their differentiation.
• Neutrophils: immune cells that are recruited when cells become damaged. They eliminate and damage tumour cells and cause inflammation by: phagocytosis, secretion of inflammatory proteins, and exocytosis of cytolytic chemicals.

Radiotherapy

How Does Radiotherapy Work?

Infrared radiation in the form of electromagnetic waves or protons is concentrated on tumour cells. The radiation then kills or inhibits the proliferation of the tumour cells through the deposition of energy inside the cells.¹ Direct ionisation of the tumour or cancerous site induces DNA damage by breaking one or two of the strands of the double helix. Accumulated cell damage eventually leads to cell death via apoptosis or cell cycle arrest.¹⁷ The effects of radiotherapy are not tumour cell-specific; therefore, damage to the surrounding organs and tissues is expected but can be minimised. This is achieved by localised irradiation, which spares as many healthy cells as possible and using fractionated treatment sessions. Modern radiotherapy has enabled greater precision which minimises irradiation to surrounding tissue.¹⁸ 

When is Radiotherapy the preferred treatment?

Radiotherapy can be used at several stages of cancer or after it has started to spread beyond a local level.¹⁹  It can be used to:

• Cure cancer completely (curative radiotherapy)
• Relieve symptoms if the cancer is incurable (palliative radiotherapy)
• Reduced the risk of relapse after surgery (adjuvant radiotherapy)
• Make other cancer treatments more effective. For example, radiotherapy can be combined with chemotherapy to optimise survival and recurrence-free survival rates (neoadjuvant radiotherapy) 

Radiotherapy is more commonly used in those with incurable cancers to control symptoms.²⁰  In addition, radiotherapy has proved successful in shrinking tumours prior to surgery, thus making the affected area easier to remove, or after surgery to remove any remnants of cancer that may remain.²¹  

Receiving Treatment (how many sessions, how long each, what happens, etc)

Most people have up to five weekly treatments, one session per weekday.²⁰ Depending on the severity and type of one’s cancer and the aim of therapy, sessions can be administered on weekends. Suppose radiotherapy is being used to help alleviate symptoms rather than cure cancer - in such a case, less than five treatments may be required per week.²⁰ One course of treatment can span 1 to 7 weeks at a time. Treatment sessions can be expected to last anywhere between 10 to 30 minutes,¹⁹ but depending on the aim of treatment or the severity of one’s condition, the duration of treatment may be less or longer.

Radiotherapy can be administered ‘externally’ or ‘internally’. The most common types²⁰ are:

• External radiotherapy: during external therapy, a patient lies on a table, and a machine concentrates a beam of high-energy infrared radiation on the cancer site. This is commonly known as conventional external beam radiotherapy. It is best to remain as still as possible throughout the treatment, which only lasts a few minutes. The machine is operated outside the treatment room, but you’ll be watched through a window or camera.
• Radiotherapy implants (internal): the use of radioactive implants is known as brachytherapy. It involves inserting temporary metal wires or tubes near the cancer site. Surgery is sometimes required to place the implant near the cancerous cells. The duration the implant is left inside the body depends on the type and the severity of your cancer. If you receive a radioactive implant, it is vital that you stay in a controlled hospital facility for a few days until the implant is removed. This is to minimise any risk to other people.
• Liquid radiotherapy (internal): radiotherapy injections, drinks, or capsules are usually recommended in thyroid and prostate cancer treatment. After radiotherapy, you will have to stay in the hospital until radioactivity decreases, as you could pose a risk to others. This radiotherapy doesn’t cause long-term harm to the body. You will be discharged from the hospital once the radiation has fallen to a safe level.
• Intrabeam radiotherapy (internal): also known as intraoperative radiotherapy, is a technique used for partial breast irradiation and inoperative boosting in patients with breast cancer.²² An X-ray beam is delivered in doses to the inner surface of the breast cavity via a needle attachment. Compared to external radiotherapy, intrabeam therapy can reduce overall treatment time, enhance patient convenience, and potentially lead to dose escalation. ²³  

Side Effects of Radiotherapy

Whilst radiotherapy kills cancerous cells, it can also damage healthy cells that surround the site of cancer. The most common side effects include:

• Fatigue: radiotherapy has been found to cause acute fatigue in 80% of patients, with chronic fatigue persisting in 30% of patients for months to years post-treatment.²⁴ The leading causes are persistent immune activation and direct effects on organ systems.²⁵ 
• Irritated skin: at the site of external irradiation, the skin can become sore, red, dry, itchy, and darker than usual. This typically starts 1 to 2 weeks after treatment begins.⁵ 
• Hair loss: one of the most common side effects of radiotherapy, it differs from chemotherapy in that hair is lost in the treated region. Hair loss begins to occur 2 to 3 weeks after treatment and should grow back within a few weeks of the treatment finishing.⁵ 
• Diarrhoea: a study found that in those receiving pelvic radiotherapy, up to 50% of patients experienced diarrhoea, rectal bleeding, urgency, and faecal incontinence.²⁶ 
• Nausea: some people feel nauseous during or after radiotherapy. It is most common in those receiving cancer treatment near the brain and abdominal regions.⁵ 
• Bloating and abdominal issues: bloating is a common side effect of radiotherapy near the abdominal region.²⁷ Abdominal interferences include carbohydrate intolerance, irritable bowel diseases, and gallstones.²⁸  
• Psychological issues: those undergoing radiotherapy have shown an increase in distress, anxiety, and depression.²⁹ 

Radiotherapy and the Immune System

Local Radiation vs. Total Body Radiation

Local radiation therapy has been shown to trigger the immune system's capacity to stimulate cell death, leading to host cell immune responses.³⁰ Irradiation of a tumorous site augments the presence of antigens on the tumour cell surface, making the cancer cell 'more visible' to the body's immune system for an attack.

On a total body level, radiation therapy creates an inflammatory cytokine response that facilitates the migration and function of CD8 T cells.³¹ Improved antigen presentation and enhanced functioning of cytotoxic T cells, therefore, provide a possible immune-mediated abscopal effect.

Radiation to lymph node area or bones can negatively impact the immune system 

The lymphatic system includes lymph nodes, ducts, and sinuses, which serve to drain excess interstitial fluid directly into the bloodstream. Lymph nodes have a significant role in the immune system, housing the greatest activity and accumulation of T and B cells.³² Damage to the lymphatic vessels occurs after radiation therapy as healthy cells develop into fibrous tissue that blocks the lymphatic flow.³³ In response to radiation, the lymph nodes become eradicated of lymphocytes, impairing local and systemic immune responses. A lack of T and B cells means the body cannot fight against cancer during radiation therapy.

Persistent irritation exposure causes a deterioration of the quantity of bone, which interferes with bone structure by increasing the activity of osteoclasts ('bone cells' that mediate bone loss) and by decreasing the activity of osteoblasts ('bone cells' that create healthy bone).³⁴ Following repeated radiation therapy, bone marrow diminishes. Stem cell and immune cell populations within bone marrow decline, making recovery less efficient.³⁵ 

Lymphoedema

​​If the lymph nodes become fibrous during radiation therapy, the ability to filter lymphatic fluid is impaired due to blockages, ultimately promoting lymphoedema.³³ Histological changes caused by radiotherapy and post-treatment inflammation can promote lymphoedema. Fibrous blockages prevent essential immune cells from circulating effectively around the body, limiting treatment efficacy and hindering treatment success and overall mortality. 

Is radiotherapy more harmful to the immune system than other cancer treatments?

All forms of cancer treatment aim to improve survival in patients. However, they all act on the body and cancer differently. Take radiotherapy and chemotherapy, for example; both are highly successful in killing cancer cells, shrinking the cancerous site, and destroying cancer. However, chemotherapy acts systemically, whereas radiotherapy is more localised.

Chemotherapy can have total body effects, impacting all of the body and cancerous cells.³⁶ Chemotherapy drugs are administered via intravenous methods or orally. These drugs target and kill cells that divide and proliferate, interfering with the cell's ability to replicate. However, some parts of the body have a fast turnover of cells, such as root hair cells, that are directly impacted by chemotherapy drugs. This leads to unwanted side effects in regions of the body without cancer.

External radiotherapy and internal intrabeam and injection radiotherapies are local treatments. The radiation is applied only to the tumour site, not on a whole body level. 

Overall, systemic treatment such as chemotherapy can have more whole-body side effects than local-level radiotherapy. But local therapies such as external radiotherapy have more severe side effects in the area of the body being treated. Treatment options should be tailored to the patient and must be adjusted according to one's symptoms if side effects are experienced.

Supporting your immune system during and after treatment 

Cancer treatment causes many side effects. Patients must receive palliative care to alleviate symptoms and reduce the treatment burden. Those receiving any treatment should seek holistic advice to ensure treatment is fully effective with the fewest possible side effects. There are a few ways in which you can support your body and immune system during and after treatment, including:

• Treating skin exposed to radiation: Patients undergoing radiotherapy will have some skin damage. Hydrophilic topicals, such as aloe vera gel or oils high in essential fatty acids, are just as effective as mild steroid creams at reducing the severity of skin damage.³⁷ 
• Maintaining a healthy, balanced diet: a diet composed of a variety of protein-rich foods, low saturated fat, and fresh fruit and vegetables helps repair damaged body cells and maintains a healthy immune system.³⁸  
• Being physically active: fatigue is one of the most common side effects of radiotherapy treatment. Research has shown that regular physical activity helps alleviate treatment-induced fatigue during and after radiotherapy.³⁹ 
• Getting sufficient sleep: exhaustion and lack of sleep from treatment make it harder to manage the stress and fatigue of radiotherapy. Enough sleep is required for treatment to be fully effective and to allow the body to repair itself.

Summary

Radiotherapy involves the external or internal administration of ionising radiation that induces DNA damage to cancerous cells. Radiotherapy has been shown to activate the body's natural immune response whilst attacking cancer cells simultaneously; it causes cell death, inhibits tumour growth, and can also activate the immune system simultaneously.⁹  All plausible treatment options should be discussed with your doctor and tailored to the patient's needs. Patients should be made aware of any likely side effects of treatment and how to best manage them during and after treatment.