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Cancer immunology (immuno-oncology) is an interdisciplinary branch ofbiology and a sub-discipline ofimmunology that is concerned with understanding the role of theimmune system in the progression and development ofcancer; the most well known application iscancer immunotherapy, which utilises the immune system as a treatment for cancer. Cancerimmunosurveillance andimmunoediting are based on protection against development of tumors in animal systems and (ii) identification of targets for immune recognition of human cancer.

Cancer immunology is an interdisciplinary branch of biology concerned with the role of theimmune system in the progression and development ofcancer; the most well known application iscancer immunotherapy, where the immune system is used to treat cancer.^[1][2] Cancerimmunosurveillance is a theory formulated in 1957 by Burnet and Thomas, who proposed thatlymphocytes act as sentinels in recognizing and eliminating continuously arising, nascenttransformed cells.^[3][4] Cancer immunosurveillance appears to be an important host protection process that decreases cancer rates through inhibition ofcarcinogenesis and maintaining of regular cellularhomeostasis.^[5] It has also been suggested that immunosurveillance primarily functions as a component of a more general process of cancer immunoediting.^[3]

Tumors may express tumor antigens that are recognized by the immune system and may induce an immune response.^[6] These tumor antigens are either TSA (Tumor-specific antigen) or TAA (Tumor-associated antigen).^[7]

Tumor-specific antigens (TSA) are antigens that only occur in tumor cells.^[7] TSAs can be products of oncoviruses like E6 and E7 proteins ofhuman papillomavirus, occurring incervical carcinoma, or EBNA-1 protein ofEBV, occurring inBurkitt's lymphoma cells.^[8][9] Another example of TSAs are abnormal products of mutated oncogenes (e.g.Ras protein) and anti-oncogenes (e.g.p53).^[10]

Tumor-associated antigens (TAA) are present in healthy cells, but for some reason they also occur in tumor cells.^[7] However, they differ in quantity, place or time period of expression.^[11] Oncofetal antigens are tumor-associated antigens expressed by embryonic cells and by tumors.^[12] Examples of oncofetal antigens areAFP (α-fetoprotein), produced byhepatocellular carcinoma, orCEA (carcinoembryonic antigen), occurring in ovarian and colon cancer.^[13][14] More tumor-associated antigens are HER2/neu, EGFR or MAGE-1.^[15][16][17]

Cancerimmunoediting is a process in whichimmune system interacts with tumor cells. It consists of three phases: elimination, equilibrium and escape. These phases are often referred to as "the three Es" of cancer immunoediting. Bothadaptive andinnate immune system participate in immunoediting.^[18]

In the elimination phase, the immune response leads to destruction of tumor cells and therefore to tumor suppression. However, some tumor cells may gain more mutations, change their characteristics and evade the immune system. These cells might enter the equilibrium phase, in which the immune system does not recognise all tumor cells, but at the same time the tumor does not grow. This condition may lead to the phase of escape, in which the tumor gains dominance over immune system, starts growing and establishes immunosuppressive environment.^[19]

As a consequence of immunoediting, tumor cell clones less responsive to the immune system gain dominance in the tumor through time, as the recognized cells are eliminated. This process may be considered akin to Darwinian evolution, where cells containing pro-oncogenic or immunosuppressive mutations survive to pass on their mutations to daughter cells, which may themselves mutate and undergo further selective pressure. This results in the tumor consisting of cells with decreasedimmunogenicity and can hardly be eliminated.^[19] This phenomenon was proven to happen as a result ofimmunotherapies of cancer patients.^[20]

• CD8+ cytotoxic T cells are a fundamental element of anti-tumor immunity. TheirTCR receptors recognise antigens presented byMHC class I and when bound, the Tc cell triggers itscytotoxic activity. MHC I are present on the surface of all nucleated cells. However, some cancer cells lower their MHC I expression and avoid being detected by the cytotoxic T cells.^[21][22] This can be done by mutation of MHC I gene or by lowering the sensitivity to IFN-γ (which influences the surface expression of MHC I).^[21][23] Tumor cells also have defects in antigen presentation pathway, what leads into down-regulation of tumor antigen presentations. Defects are for example intransporter associated with antigen processing (TAP) ortapasin.^[24] On the other hand, a complete loss of MHC I is a trigger forNK cells.^[25] Tumor cells therefore maintain a low expression of MHC I.^[21]
• Another way to escape cytotoxic T cells is to stop expressing molecules essential for co-stimulation of cytotoxic T cells, such asCD80 orCD86.^[26][27]
• Tumor cells express molecules to induce apoptosis or to inhibitT lymphocytes:
  • Expression ofFasL on its surface, tumor cells may induceapoptosis of T lymphocytes by FasL-Fas interaction.^[28]
  • Expression ofPD-L1 on the surface of tumor cells leads to suppression of T lymphocytes byPD1-PD-L1 interaction.^[29]
• Tumor cells have gained resistance to effector mechanisms ofNK andcytotoxic CD8+ T cell:
  • by loss of gene expression or inhibition of apoptotic signal pathway molecules:APAF1,Caspase 8,Bcl-2-associated X protein (bax) andBcl-2 homologous antagonist killer (bak).^[30][31]
  • by induction of expression or overexpression of antiapoptotic molecules:Bcl-2,IAP orXIAP.^[32][33]

• Production ofTGF-β by tumor cells and other cells (such asmyeloid-derived suppressor cell) leads to conversion ofCD4+ T cell into suppressiveregulatory T cell (Treg)^[34] by a contact dependent or independent stimulation. In a healthy tissue, functioning Tregs are essential to maintain self-tolerance. In a tumor, however, Tregs form an immunosuppressive microenvironment.^[35]
• Tumor cells produce special cytokines (such ascolony-stimulating factor) to producemyeloid-derived suppressor cell. These cells are heterogenous collection of cell types including precursors ofdendritic cell,monocyte andneutrophil. MDSC have suppressive effects onT-lymphocytes, dendritic cells andmacrophages. They produce immunosuppressiveTGF-β andIL-10.^[36][25]
• Another producer of suppressiveTGF-β andIL-10 aretumor-associated macrophages, these macrophages have mostly phenotype of alternatively activatedM2 macrophages. Their activation is promoted byTH type 2 cytokines (such asIL-4 andIL-13). Their main effects are immunosuppression, promotion of tumor growth andangiogenesis.^[37]
• Tumor cells havenon-classical MHC class I on their surface, for exampleHLA-G. HLA-G is inducer of Treg, MDSC, polarise macrophages into alternatively activated M2 and has other immunosuppressive effects on immune cells.^[38]

Immune system is the key player in fighting cancer. As described above in mechanisms of tumor evasion, the tumor cells are modulating the immune response in their profit. It is possible to improve the immune response in order to boost the immunity against tumor cells.

• monoclonal anti-CTLA4 and anti-PD-1 antibodies are calledimmune checkpoint inhibitors:
  • CTLA-4 is a receptor upregulated on the membrane of activated T lymphocytes, CTLA-4CD80/86 interaction leads to switch off of T lymphocytes. By blocking this interaction with monoclonal anti CTLA-4 antibody we can increase the immune response. An example of approved drug isipilimumab.
  • PD-1 is also an upregulated receptor on the surface of T lymphocytes after activation. Interaction PD-1 withPD-L1 leads to switching off orapoptosis. PD-L1 are molecules which can be produced by tumor cells. The monoclonal anti-PD-1 antibody is blocking this interaction thus leading to improvement of immune response in CD8+ T lymphocytes. An example of approved cancer drug isnivolumab.^[39]
  • Chimeric Antigen Receptor T cell
    • This CAR receptors are genetically engineered receptors with extracellular tumor specific binding sites and intracellular signalling domain that enables the T lymphocyte activation.^[40]
  • Cancer vaccine
    • Vaccine can be composed of killed tumor cells, recombinant tumor antigens, or dendritic cells incubated with tumor antigens (dendritic cell-based cancer vaccine)^[41]

Obeid et al.^[42] investigated how inducing immunogenic cancer cell death ought to become a priority of cancer chemotherapy. He reasoned, the immune system would be able to play a factor via a 'bystander effect' in eradicating chemotherapy-resistant cancer cells.^{[43][44][45][2]} However, extensive research is still needed on how the immune response is triggered against dying tumour cells.^[2][46]

Professionals in the field have hypothesized that 'apoptotic cell death is poorly immunogenic whereasnecrotic cell death is truly immunogenic'.^[47][48][49] This is perhaps because cancer cells being eradicated via a necrotic cell death pathway induce an immune response by triggering dendritic cells to mature, due to inflammatory response stimulation.^[50][51] On the other hand, apoptosis is connected to slight alterations within the plasma membrane causing the dying cells to be attractive to phagocytic cells.^[52] However, numerous animal studies have shown the superiority of vaccination with apoptotic cells, compared to necrotic cells, in eliciting anti-tumor immune responses.^{[53][54][55][56][57]}

Thus Obeidet al.^[42] propose that the way in which cancer cells die during chemotherapy is vital.Anthracyclins produce a beneficial immunogenic environment. The researchers report that when killing cancer cells with this agent uptake and presentation by antigen presenting dendritic cells is encouraged, thus allowing a T-cell response which can shrink tumours. Therefore, activating tumour-killing T-cells is crucial for immunotherapy success.^[2][58]

However, advanced cancer patients with immunosuppression have left researchers in a dilemma as to how to activate their T-cells. The way the host dendritic cells react and uptake tumour antigens to present to CD4⁺ and CD8⁺ T-cells is the key to success of the treatment.^[2][59]

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• Branches of immunology

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