The immune system performs immunosurveillance to detect and eliminate abnormal cells within the body. This protective mechanism is highly effective at destroying nascent cancer cells before they can develop into a full tumor. However, cancer cells are transformed cells that have acquired the ability to bypass this immune detection and destruction. This complex process, termed immunoevasion, involves sophisticated strategies that allow the malignancy to persist and grow unchecked.
Concealing Tumor Identity
The first step in evading the immune system involves making the cancer cell “invisible” to cytotoxic T-cells. T-cells identify threats by scanning for abnormal protein fragments, or antigens, displayed on the cell surface. These fragments are presented by Major Histocompatibility Complex Class I (MHC-I) molecules, which act like a cell’s identification tag.
In many cancers, cells lose or significantly reduce the expression of MHC-I molecules (MHC-I downregulation). This loss means that even if the cell contains tumor-associated antigens (TAAs), the T-cell cannot detect the threat. The machinery responsible for processing and loading antigens onto MHC-I molecules can also be compromised, preventing the display of the danger signal. Additionally, a tumor can stop producing the specific TAAs that initially triggered an immune response. This failure of antigen presentation is a fundamental form of immune evasion.
Activating Immune Checkpoints
Even if a T-cell recognizes a cancer cell, the tumor employs a second strategy to shut down the immune attack through molecular signaling. This involves exploiting natural “brakes” in the immune system known as immune checkpoints. These proteins normally regulate the duration and intensity of an immune response, preventing the immune system from damaging healthy tissue.
The most well-known checkpoint axis is the Programmed Death-1 (PD-1) pathway, where the cancer cell expresses PD-Ligand 1 (PD-L1). When PD-L1 on the tumor cell connects with the PD-1 receptor on the T-cell, it sends a “do not attack” signal. This interaction deactivates the T-cell, causing it to enter a state of exhaustion or anergy where it can no longer proliferate or kill the cancer cell.
Another important brake is the Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4) mechanism, which primarily acts earlier in the immune response in the lymph nodes. CTLA-4 is expressed on the T-cell surface and competes with the activating receptor CD28 for binding to B7 molecules on antigen-presenting cells. By preferentially binding to B7, CTLA-4 delivers an inhibitory signal that limits the initial activation and proliferation of T-cells. Cancer cells manipulate this pathway to ensure the immune response is suppressed before it gains momentum.
Building an Immunosuppressive Microenvironment
Cancer actively manipulates the local environment, known as the tumor microenvironment (TME), to create an atmosphere that suppresses the immune response. The tumor and surrounding cells secrete immunosuppressive chemical messengers, or cytokines, that dampen the inflammation necessary for a successful attack. Transforming growth factor-beta (TGF-\(\beta\)) and Interleukin-10 (IL-10) are two cytokines that suppress the function of cytotoxic T-cells and natural killer (NK) cells.
The cancer recruits and fosters the growth of specific immune cell populations within the TME. Regulatory T-cells (Tregs) are a type of T-cell that naturally works to maintain immune tolerance. However, tumors accumulate Tregs, which release high levels of immunosuppressive factors like IL-10 and TGF-\(\beta\), paralyzing nearby anti-tumor immune cells.
The TME is often rich in Myeloid-Derived Suppressor Cells (MDSCs), an immature and highly inhibitory population of immune cells. MDSCs use multiple mechanisms, including the depletion of essential nutrients and the production of suppressive enzymes, to inhibit the function of T-cells and NK cells. This combined action establishes a localized shield that prevents the immune system from mounting a sustained anti-tumor assault.
Resisting Immune-Mediated Destruction
Even when a cytotoxic T-cell or Natural Killer cell bypasses evasion mechanisms and attacks the cancer cell, the tumor often possesses internal defenses to survive. The primary way immune cells kill targets is by triggering apoptosis, or programmed cell death. Cancer cells frequently develop resistance to this induced death signal.
One common strategy is the upregulation of anti-apoptotic proteins, such as those in the Bcl-2 family, which block the cell’s self-destruct mechanism. By overexpressing these proteins, the cancer cell neutralizes the pro-death signals delivered by the immune system. Cancer cells also evade death by downregulating “death receptors” on their surface, such as the Fas receptor, which are targets of immune attack molecules.
In another defense, the cancer cell neutralizes toxic molecules released by attacking T-cells, such as perforin and granzymes. Perforin creates pores in the cell membrane, allowing granzyme to enter and trigger cell death. Some tumor cells increase the secretion of enzymes like Cathepsin B, which degrade perforin before it breaches the cell’s defenses.