Tumour-infiltrating lymphocytes, or TILs, are the body’s own immune cells that have left the bloodstream to enter and attack cancerous tumours. Their presence within a tumour is a direct reflection of the body’s attempt to control cancer growth. This dual role as both a naturally occurring defense and a foundation for advanced cancer treatments places TILs at the forefront of modern oncology.
Composition and Function Within the Tumour
The TIL population is a diverse assembly, primarily composed of T-cells, which are specialized white blood cells. The most prominent are CD8+ cytotoxic T-lymphocytes, which act as the primary soldiers in the fight against cancer by directly identifying and eliminating tumour cells. They are supported by CD4+ helper T-cells, which coordinate the anti-tumour response by activating and directing other immune cells.
Beyond the T-cell populations, other immune cells contribute to the anti-tumour environment. Natural Killer (NK) cells are another type of lymphocyte that can kill tumour cells without prior sensitization. B-cells are also found within tumours, where they can help by producing antibodies and presenting tumour antigens to T-cells, further stimulating the immune attack.
The process by which TILs target cancer relies on their ability to recognize specific molecules on the surface of tumour cells called antigens. CD8+ T-cells use their T-cell receptors to bind to these antigens, a process often compared to a lock and key mechanism. Once this recognition occurs, the T-cell becomes activated and releases potent substances, such as perforin and granzymes. These create pores in the tumour cell membrane and trigger its self-destruction.
Prognostic Significance in Cancer
The presence and characteristics of TILs within a tumour can provide valuable information about a patient’s likely disease course, a concept known as prognostic significance. By examining the immune cells in a tumour biopsy, doctors can make a more informed prediction about the patient’s outcome. A high density of these immune cells often signals a more robust anti-tumour immune response.
This observation has led to the classification of tumours into “hot” and “cold” categories. Hot tumours are those heavily infiltrated with TILs, particularly the cancer-killing CD8+ T-cells. The abundant presence of these lymphocytes is often associated with a better prognosis, as it indicates the immune system is actively engaged in fighting the cancer and can slow tumour growth.
Conversely, “cold” tumours have few or no TILs present. This lack of immune infiltration suggests the body’s defense system has failed to recognize or penetrate the tumour, which often correlates with a poorer prognosis. The location of the TILs also matters; lymphocytes found deep within the tumour mass (intratumoural) are a better prognostic sign than those confined to the surrounding tissue (peritumoural). The ratio of different T-cell types, such as a high ratio of CD8+ T-cells to suppressive regulatory T-cells, can also be a predictor of survival.
Adoptive Cell Therapy Using TILs
Beyond their prognostic role, TILs are harnessed directly as a cancer treatment known as adoptive cell therapy. This approach involves collecting a patient’s own tumour-fighting lymphocytes and expanding their numbers in a laboratory before returning them to the body. This therapy amplifies the patient’s existing immune response, creating an army of cells primed to attack their cancer.
The process begins with the surgical removal of a portion of the patient’s tumour. From this tissue, the TILs are isolated from the cancer cells and other components. These selected lymphocytes, which have already demonstrated an ability to recognize the tumour, are then cultured in a laboratory with growth factors like Interleukin-2 (IL-2). This step stimulates the cells to multiply rapidly over several weeks, expanding a small population into billions of cells.
Once this army of TILs is ready, the patient undergoes a short course of chemotherapy known as lymphodepletion. This procedure is not intended to kill the cancer but to reduce the number of other existing lymphocytes in the body. This makes biological space for the newly infused TILs and reduces competition, allowing them to mount a more effective attack. Following this preparation, the expanded TILs are infused back into the patient’s bloodstream to travel to the tumour sites. This strategy has shown success, particularly in patients with metastatic melanoma.
Factors Influencing TIL Effectiveness
The success of TILs, whether occurring naturally or as therapy, is not guaranteed because tumours have developed methods to protect themselves. The environment within a tumour, often called the tumour microenvironment, contains numerous obstacles that can hinder TIL function. These challenges explain why some immune responses fail and TIL therapy is not effective for every patient.
One hurdle is tumour evasion, where cancer cells hide from the immune system. They can achieve this by reducing the expression of the surface antigens that TILs use for recognition. Additionally, tumour cells can express proteins on their surface, such as PD-L1, which act as “off switches” when they bind to corresponding receptors like PD-1 on T-cells. This interaction deactivates the T-cells, halting the immune attack.
Another issue is T-cell exhaustion. After prolonged exposure to tumour antigens and a sustained fight, TILs can become functionally worn out. Exhausted T-cells lose their ability to produce the necessary molecules to kill cancer cells and to multiply effectively. This state is often characterized by the high expression of multiple inhibitory receptors on the T-cell surface.
Finally, the tumour microenvironment often contains other immune cells that actively suppress the anti-tumour response. A primary group of these are regulatory T-cells, or Tregs. While Tregs normally help prevent autoimmune reactions, in cancer, they can accumulate within the tumour and release signals that inhibit the function of the cancer-killing CD8+ T-cells. This active suppression can neutralize the effectiveness of a strong TIL presence.