Introduction

Oral cancer is a serious health concern that affects hundreds of thousands of people globally each year. The immune system is in charge of identifying and eliminating abnormal cells, including cancer cells. It is well known that the immune system plays an important role in protecting against oral cancer and inefficiencies in the immune system function can facilitate cancer development and growth. That is why it is important to understand the connection between oral cancer and immune system function so that we can better prevent and manage this devastating disease.  In this article, we will explore the definition of oral cancer, introduce the immune system, and most importantly, discuss the link between them.

What is oral cancer?

Oral cancers are a part of a larger cancer group, known as head and neck cancers. Oral cancers develop in the mouth and oropharynx areas, which include:

• The lips and gums
• The tongue
• The inner lining of your lips and cheeks (buccal mucosa)
• The area below your tongue (floor of the mouth)
• The roof of your mouth (hard and soft palate)
• The small area behind your wisdom teeth (retromolar trigone)
• The area of the throat at the back of your mouth (oropharynx)

The proportions of different areas affected by oral cancer are estimated to be around 32% in the buccal mucosa, 22% in the tongue, 11% in the lower lip, 11% in the roof of the mouse, 8% in the vestibule (space between lips/cheeks and gums/teeth), 5% in dental alveolus (tooth socket), 5% in the floor of the mouth, and 3% in gums.¹

The most common type of oral cancer is squamous cell carcinoma, accounting for around 90% of all cases. Other types of oral cancer, which are less common, include oral malignant melanoma (cancer starts in melanocytes, which are cells that give skin its colour) and adenocarcinomas (cancers that start inside the salivary glands).

According to WHO, the global occurrence of oral cancer was estimated to be 377,713 new cases and 177,757 deaths in 2020, and it ranks as the 13th most common cancer. Meanwhile, the American Cancer Society’s estimates for 2024 in the USA are 58450 new cases and about 12230 deaths from oral cancers. Furthermore, the Oral Health Foundation estimates that 8846 new cases of oral cancer and 3034 deaths resulting from oral cancer occur annually in the UK.

Oral cancers are more common in men and older people, with higher fatality rates observed in men compared to women. Socio-economic factors strongly influence these disparities, with higher occurrences noted in countries like India, Taiwan, Sri Lanka, Pakistan, and Bangladesh. ^1,2

Risk factors of oral cancer

The main risk factors of oral cancer are:³

• Tobacco use (includes cigarettes, cigars, pipes and smokeless tobacco, such as snuff) – tobacco has multiple carcinogens, which can cause important mutations involved in DNA replication and DNA damage
• Betel quid chewing – it is a common habit in Southeast Asia, in particular in the Indian subcontinent. It commonly contains leaves of the Piper betel vine, areca nut, slaked lime, and tobacco. Studies have shown that betel quid chewing is associated with oral cancer and precancerous conditions
• Alcohol – alcoholic beverages are considered to be carcinogenic and are associated with oral cancers. Using alcohol and tobacco together can even further increase the risk of oral cancer development
• Diet – diet can affect our risk of developing certain diseases, including oral cancer. For instance, increased consumption of fruits and vegetables, as well as fibre, is associated with reduced risk of oral cancer.^4,5 Meanwhile, some foods are associated with an increased risk of oral cancer, such as processed meats, cakes and desserts, butter, eggs, red meat, salted meat, cheese, pulses, pasta or rice³
• Mouthwash – mouthwashes have also been considered as one of the factors that may increase the risk of oral cancer. No cause-and-effect relationship has been established between cancer and mouthwash. However, mouthwash often contains alcohol and the risk assigned to mouthwash correlates with frequency and duration of use as well as its alcohol content
• Viral infection – viruses, which have been associated with oral cancer development, are human herpesvirus (particularly Epstein–Barr virus (EBV)), human papillomavirus (HPV), and herpes simplex virus (HSV)
• UV/sun exposure – high levels of sun exposure can increase the risk of lip cancer
• Radiation – ionising radiation has been implicated in the development of salivary gland cancers
• Genetics – genetic predisposition is another important risk factor. Inheriting certain defects in genes can increase your risk of oral cancer development

Signs and symptoms

Some of the common symptoms of oral cancer are:

• A sore, lump or thick patch in your mouth, lip, or throat
• A white or red patch in your mouth
• Sore throat, feeling like there is something caught in your throat, or hoarseness or loss of your voice
• A lump in the neck
• Difficulty chewing, swallowing, or speaking
• Difficulty moving your jaw or tongue
• Swelling of your jaw may cause your dentures to fit poorly
• Pain or bleeding in your mouth
• Numbness in your tongue or other parts of your mouth or throat
• Ear pain

Overview of the immune system

The immune system is made up of multiple organs, cells and proteins that work together to protect you from harmful substances, germs and changes in the cells that could make you unwell.

Your immune system is made up of two main parts that work together:

• The innate immune system - You are born with this. It provides general defence and is considered non-specific⁶
• The adaptive immune system - You develop this when your body is exposed to germs and harmful substances. It is considered specific as it makes antibodies that fight specific germs⁶

Main functions of the immune system

The main responsibilities of the immune system are:

• Fighting pathogens that cause diseases, such as bacteria, viruses, parasites or fungi
• Recognising and neutralising harmful substances
• Fighting changes in the body that cause diseases, such as cancer cells

The way the immune system works when it is functioning properly is by:

• Telling the difference between cells that belong in your body and those that should not be in your body
• Activating and mobilising the immune cells to kill germs that can harm you
• Ending an attack (by the immune system) once the threat is over
• Learning about the germs after you have come across them, and developing antibodies against them
• Sending out antibodies to kill germs, trying to enter your body

Interaction between oral cancer and the immune system

The immune system has a complicated role in cancer. In general, your immune system works to protect you against cancer, but sometimes things can go wrong: your immune system can weaken and no longer be able to protect you, or sometimes, your immune system can even work against you and help the cancer grow.⁷

How does your immune system protect you from oral cancer?

When the immune system detects cancerous cells, it induces something called the host immune response, which prevents cancer cells from growing and spreading. This process is known as immune surveillance.⁸ One of the types of immune cells that play a key role in preventing cancer development is the T lymphocyte. Cancers can activate highly specific CD8+ T lymphocytes and CD4+ T lymphocytes. CD8+ T cells directly kill cancer cells, while CD4+ T cells stimulate the cancer-killing effect of CD8+ T cells by releasing cytokines, proteins that act as chemical messengers in your immune system.⁹ Another type of immune cell that helps prevent cancer is the natural killer (NK) cell. NK cells also kill cancer cells and limit the metastasis of cancerous cells.⁹ Dendritic cells (DCs) are also immune cells that have anti-cancer functions. DCs can recognise cancers and direct CD8+ T cells to them as well as activate NK cells.⁹

Your immune system has a robust process to prevent cancer from developing in your body, however, some diseases and medications can make your immune system weaker. There is an increased risk of developing oral cancer in people:

• People who have HIV/AIDS – HIV weakens your immune system. HPV infection is more common in people with HIV
• People who are taking medicines to suppress the immune system after an organ transplant

The immune system also weakens with age as there is a decrease in cell-mediated immune response, which, in turn, increases the risk of cancer development.¹⁰

How can your immune system help oral cancer grow?

Cancer cells can learn how to evade immune surveillance. Cancer cells can release immunity-suppressing cytokines, which may cause immune surveillance to fail so that cancer cells can grow and spread.⁸

Furthermore, factors released by cancer cells can promote immune cells to suppress the immune system's response to cancer and help cancer grow and spread.¹¹ One cell type that promotes cancer growth is known as tumour-associated macrophages (TAMs). TAMs are a subgroup of macrophages which suppress immune system responses and can destroy T cells.¹² TAMs can also prevent DC cells from properly developing.⁹ Another type is Treg cells, which are a subtype of CD4+ T, and they can inhibit the activation of the cancer-killing effect of CD8+ T cells as well as other immune cells.⁹ Other immune cell types promote tumour development, such as myeloid-derived suppressor cells and tumour-associated neutrophils.¹¹

How can your immune system be used to treat cancer?

Some types of cancers, including oral cancer, can be treated with immunotherapy. Immunotherapy works by enhancing our immune system's response to cancer, helping it recognise and attack cancer cells.¹³ You might have immunotherapy as a sole type of treatment or together with other types of cancer treatment. There are several different types of immunotherapy, which include:

• Monoclonal antibodies – they are very similar to antibodies that our bodies produce. Monoclonal antibodies can recognise certain proteins on cancer cells and attach to them, which can trigger an immune response
• Checkpoint inhibitors – checkpoints are a normal part of the immune system, which prevent immune cells from having an effect that is too strong. Cancers can use this mechanism to their advantage and suppress the immune response. Checkpoint inhibitors block checkpoints from being able to prevent the immune response to cancers
• Vaccines – vaccines can be created to recognise certain proteins in cancer cells, which helps the immune system recognise and attack these cells
• Cytokines – some cytokines can promote a cancer-fighting immune response
• CAR-T cell therapy – T cells are genetically engineered to help them recognise and attack cancer cells

Summary

Oral cancer is a serious type of cancer, which ranks as the 13^th most common cancer worldwide. Oral cancers can affect different areas of the mouth and throat. Anyone can develop oral cancer; however, some risk factors increase the risk, such as the use of tobacco or alcohol, betel quid chewing, inappropriate diet, genetic predisposition and excessive sun exposure. Usually, the immune system protects you from germs, harmful substances and cancers. However, there are times when the immune system may weaken, due to medication or illness, and can no longer provide adequate protection. Furthermore, cancer can trick the immune system into helping it grow and spread. This is why immunotherapies are important in the treatment of cancer. Immunotherapies can enhance your immune system responses and help the immune system fight off cancer.