Tumour surveillance theory

In 1909, Paul Ehrlich proposed a mechanism of the immune system in eradicating aberrant cells, preventing them from developing into tumours. During the mid-20th century, scientists found experimental evidence supporting the immune system's ability to suppress tumours. This included Ludwik Gross's first findings on the immune response stimulation against sarcoma in mice in 1953, as well as E.J. Foley's research on tumours induced by methylcholantrene in that same year. The tumour surveillance theory, developed in the late 1950s by Lewis Thomas and Sir Frank MacFarlane Burnet, emerged from these findings. Thomas and Burnet hypothesised that the immune system can recognise tumour-specific neoantigens expressed on tumour cells and eliminate newly arising tumours. In 2002, Gavin P. Dunn and Robert D. Schreiber introduced the concept of immunoediting to highlight the connection between the immune system and cancer formation. Immunoediting consists of three phases: elimination, equilibrium, and escape. Elimination presents the core of the tumour surveillance theory where the immune system actively destroys tumour cells. During the equilibrium phase, tumours remain dormant, balancing between elimination and progression. Once the tumours evade the immune system and reach the third phase, they become clinically detectable. == Cancer immunosurveillance mechanism ==

According to the theory, the detection and subsequent elimination of neoplastic cells are built on the functions of several immune cells and mediators. By releasing cytotoxic granules NK cells release cytotoxic granules containing perforins and granzymes. The glycoprotein, perforin, is responsible for creating pores in target cell membranes, allowing the entry of the serine protease called granzyme. This entry triggers the apoptosis of the target cells. Additionally, cytokines for cell signalling released by NK cells, including tumour necrosis factor alpha (TNFα) and interferon-gamma (IFNγ), subsequently inducing cell destruction. NK cells are considered key effector cells triggering ADCC. Since NK cells only possess activating FcγR but not inhibitory ones, NK cells interact more effectively with the IgG antibodies than the other effector cell lineages., tumour-specific antigens, and naive then activated T cells. Cancer-immunity cycleThis cycle illustrates the importance of the activation of CD8+ for eliminating the tumour cells. Infiltration of TME by CD8+ improves cancer prognosis, and enables the prediction of many cancer developments. In the TME, B cells are also capable of recognising antigens, serving as APCs that interact with and signal the activation of other immune cells. Inflammatory cytokines released by B cells also promote the recruitment of immune cells. The antibody production ability of B cells is another potential mechanism in removing tumour cells. Upon activation of naive B cells when presented with tumour antigens, they proliferate and differentiate into plasma cells (PCs). These cells produce tumour-specific IgG-type antibodies, inducing the ADCC response in NK cells and T cells. == Evidence for and against the theory ==

Supporting evidence In transplantation mice models when tumours were transplanted into syngeneic hosts, hosts with the same genetic material, the tumour was rejected and attacked by the immune system. However, when normal tissue was transplanted, it was accepted by the hosts, this suggests the presence of tumour-specific antigens that the immune system recognises. Additionally, a decline in immunosurveillance capacity and increased accumulation of senescent cells as individuals age could explain the interplay between ageing and cancer development. A longer survival time has also been observed in patients of various tumour types including melanoma, breast, bladder, prostate, and others when more lymphocytes and NK cells were present and circulating in their body. This would corroborate the theory as well since APCs process and present neoantigens to immune cells, generating memory cells that can recognise and subsequently destroy tumour cells. Similarly, NK cells were able to attack tumour cells without previously being exposed to the cells from specific tumours. The immune evasion ability of tumour cells is supported by observations of TME inflammatory cells escaping the immune system and contributing to tumour growth in head and neck cancers. Opposing evidence In athymic nude mice, mice without T cells, more tumour growth in the absence of immunosurveillance regulation would be expected if the tumour surveillance theory is valid. However, they do not have more methylcholantrene-induced tumours than regular mice. == Alternative theories ==

There are some alternative theories suggested to tumour immunosurveillance. They include non-immune surveillance mechanisms and integrated surveillance models. Whereas integrated surveillance models are based on the synergistic effects of immune and non-immune mechanisms. DNA repair deficiencies combined with immune evasion, or epigenetic dysregulation with TME alterations. The interaction of genetic and intracellular surveillance may also pose cancer risks. These theories demonstrate how cancer involves a network of mechanisms both immune and non-immune, and the control of oncogenesis is not as simple as the consideration of tumour surveillance theory alone. == Clinical implications ==

Cancer markers Immunosurveillance is considered important in controlling tumour growth while they proliferate and mutate to become less antigenic. If the theory is true, understanding cancer cells' mechanisms for evading the immune system and being able to locate them would be crucial to preventing cancer progression or to use as a cancer marker. The presence of tumour-infiltrating lymphocytes (TILs) and specific immune markers can also serve as prognostic indicators in various cancers, such as melanoma and colorectal carcinoma. Anti-tumour antibodies While the mechanisms that cause the production of anti-tumour antibodies are still unclear, cellular and humoral immune responses against neoantigens have been recorded to produce antibodies in cancer patients. Cancer immunotherapies In modern medicine, there are already immunotherapies developed and being developed for cancer. Cancer immunotherapies are administered by injecting anti-tumour antibodies into patients and are designed to reactivate or enhance the body's immunosurveillance mechanism to target cancer cells and overcome tumour cells' immune evasion. Multispecific antibodies are also emerging as a new approach for more complex immune-evading cancers. Although the existing identified biomarkers are insufficient for treatment due to tumour heterogeneity resulting in some patients responding well to cancer immunotherapies while others do not, further research into tumour immunology and immunotherapy shows promise in improving immunotherapies, patient outcomes, and reducing adverse events. == References ==