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In recent decades, the amount of scientific knowledge available related to cancer has grown exponentially. The publication of the Hallmarks of Cancer deserves a special highlight in this history and its revision provided further insight into the main features of cancer cells and reflected the advances in research so far.
The hallmarks are still an extremely valuable framework for researchers across the world and an invaluable contribute to our understanding of the pathology of cancer. Each hallmark offers numerous research opportunities but also several therapeutic targets, which are currently being explored.
The present review focuses on one of the hallmarks, the ability of cancer cells to avoid immune detection, explores a three-step model to explain the concept of immunoediting shedding light on the mechanisms of immune avoidance and the possible therapy approaches that rise from this knowledge, such as targeted immunotherapy and novel developments that include molecular and cellular therapy and oncolytic vaccines.
Introduction
After decades of cancer research, a large pool of scientific knowledge has been produced, describing this disease as a product of the interaction between dynamic genetic changes and environmental stimuli.
The foundation for the claim regarding changes in the genome was laid out with the discovery of changes in oncogenes that often lead to their permanent activation and the loss of function of tumour suppressor genes, which lead to the development of cancer phenotypes in animal and human cell models.
Due to the complexity of the topic and the range of scientific literature available, in 2000, Hanahan and Weinberg published the Hallmarks of Cancer, with their belief that cancer research would become a logical science and aiming for it to be understood in terms of a small number of underlying principles .
In their paper, they listed the six hallmarks of cancer cells: evading apoptosis, self-sufficiency growth signals, insensitivity to anti-growth signals, tissue invasion and metastasis potential, sustained angiogenesis and limitless replicative potential.
In 2011, in light of new knowledge building up over the last decade, the authors published a revision to their previous work, adding two new hallmarks (deregulating cellular energetics and avoiding immune destruction) and also describing two enabling characteristics (tumour-promoting inflammation and genome instability and mutation), essential to tumour proliferation. In fact, as stated by Hanahan and Weinberg, the biology of tumours can no longer be understood simply by enumerating the traits of the cancer cells but instead must encompass the contributions of the tumour microenvironment to tumorigenesis .
After the publication of the new Hallmarks, several scientists have researched individual traits of cancer cells and established molecular, cellular and biochemical mechanisms in which they lead to the development of malignant tumours.
Currently, an interesting research approach adopts an evolutionary perspective and details the role of genetics, environmental stimuli and epigenetics in the acquisition of said hallmarks by cells, leading to their transformation into malignant cancer cells.
The present review will focus on the new hallmark ability of cancer cells to evade immune detection and the current applications of this knowledge in terms of cancer therapy.
The role of the immune system in detecting and eliminating potential cancer cells
Immunosurveillance as a concept, was initially proposed in 1909 by Ehrlich, who suggested that tumours are continuously detected and eliminated by the immune system, before any obvious clinical manifestations.
With advances in genetics, in 1970, the concept of immunosurveillance was further explained by Burnet, who theorised that genetic changes leading to malignancy happen frequently in somatic cells and that the immune system identifies and eliminates these potentially harmful cells.
This idea has been supported by extensive evidence and studies showing how immunodeficient mice and humans are more prone to the development of malignant tumours. Also, HIV positive patients and patients receiving immunosuppressive therapy after organ transplantation show a high incidence of malignancies.
Despite this, it is possible to observe the development of malignancies in individuals with a fully functional immune system.
Recently, the concept of immunoediting as been proposed as a dynamic process that involves three steps: elimination, equilibrium and escape.
Immunoediting: Elimination
Currently, an abnormal innate and adaptative immune response has been identified as integral part of tumorigenesis by selecting aggressive clones of cancer cells, decreasing the strength of the immune response and allowing proliferation and metastasis.
The innate immune response includes effectors such as natural killer cells (NK) and ³´ T cells, which are activated by inflammatory cytokines secreted by tumour cells, macrophages and stromal cells that surrounded the tumour.
These cytokines recruit other chemicals such as interleukin-12 (IL-12) and NK cells act via release of perforin, Fas Ligand (FasL) induced apoptosis and tumour necrosis factor-related apoptosis inducing ligand (TRAIL), which releases tumour antigens, able to active adaptative immune response.
³´ T cells also respond to stress-induced molecules on tumour cells and secrete cytotoxic molecules, inflammatory cytokines and activate adaptive immunity cells (CD4+ helper T cells, CD8+ cytotoxic T cells). They can also lyse tumour cells by antibodydependent cellular cytotoxicity (ADCC), secrete interferon gamma (IFN-³) and IL-17, upregulating other cytotoxic cells, in a positive feedback loop.
Cancer and pre-cancer cells can evade immune detection mainly by loss of antigenicity and/or formation of an immunosuppressive tumour microenvironment. Loss of antigenicity is linked to under expression of tumour antigens and the immunosuppressive microenvironment is thought to be caused by the release of IL-10 and transforming growth factor-b (TGF-b), inhibiting the activation of effector cells.
Immunoediting: Equilibrium
Equilibrium can be seen under the light of natural selection. This means that after the elimination stage, tumour cells that are highly immunogenic are destroyed, leaving the ones that induce less potent immune responses behind. This eventually leads to the selection of tumour cells with reduced immunogenicity thus explaining the apparent paradox of tumours developing in immunocompetent individuals.
Tumours that are less immunogenic can be produced by random mutations, however the action of the hosts immune system cannot be ignored. In fact, a study shown that induced sarcomas in immunodeficient mice were more immunogenic than similar tumour cells in mice with functional immune systems. This finding was attributed to the selection process that happened in the immunocompetent mice, leading to the proliferation of tumour cells resistant to immune destruction.
Immunoediting: Escape
Several mechanisms have been recognised in the escape stage, including alterations in cell signalling molecules on effector cells, alteration of tumour microenvironment and immunological ignorance and tolerance.
Importantly, the loss of signal transducer CD3-¶ chain, in the T cell receptor (TCR) leads to the loss of activation of T cells by disrupting the formation of the complex TCR-CD3, which in turn will lead to poor activation and proliferation of effector T cells. This mutation has been linked to several types of malignancies such as pancreatic cancer and ovarian cancer.
Changes to the microenvironment are mediated by a range of tumour derived soluble factors, which form a vast immunosuppressive environment such as the vascular endothelial growth factor (VEGF), IL-10, prostaglandin E2, phosphatidylserine, Fas/FasL and soluble major histocompatibility complex class I chain-related molecule A (MICA). These factors can actually have an effect on the surrounding lymph nodes and spleen, promoting formation of metastasis.
VEGF recruits immature cells from the bone marrow such as dendritic cells and macrophages, which inhibit the activity of mature dendritic and T cells due to activation of indoleamine 2,3-dioxygenase. Furthermore, VEGF suppresses nuclear factor ºB, blocking differentiation and maturation of dendritic cells, which directly down-regulates the hosts immune response.
Soluble phosphatidylserine, which can induce an anti-inflammatory response, is also upregulated in tumour cells, leading to the expression of IL-10 and transforming growth factor- ² (TGF-²), causing inhibition of dendritic cells and T cells response.
Finally, the expression of FasL and tumour necrosis factor (TNF)- related apoptosis inducing ligand (TRAIL) is upregulated in tumour cells, leading to apoptosis in Fas-expressing lymphocytes and T cytotoxic cells, respectively.
Cancer immunotherapy
Cancer immunotherapy has recently been recognised as essential and specific cancer therapy, complementing the action of more non-specific therapies, such as surgery, chemotherapy and radiotherapy. Cancer immunotherapy is based on three different approaches, listed below.
Molecular Therapy
IL-2 promotes T cell growth and is approved for treatment of metastatic renal cell carcinoma and melanoma. IL-2 increases the amount of tumour infiltrating lymphocytes, supports their growth and activation after adoptive transfer to patients. To note that side effects include vascular leak syndrome, pulmonary oedema, hypertension and heart toxicity, so care must be taken with this approach.
In order to achieve continuous activation of T cells, drugs that block the inhibitory checkpoints of the immune response are also used. As an example, ipilimumab, an anti-cytotoxic T lymphocyte associated protein 4 (anti-CTLA-4) is indicated in the treatment of kidney, bladder, head and neck cancer and Hodgkins lymphoma.
Cellular Therapy
Adoptive T cell therapy involves growing in vitro patient-derived T cells, with specificity for the tumour cells antigens and re-infusing them into patients.
As an example, chimeric antigen receptor T cell therapy (CAR-T) has shown promising results in haematological malignancies. The therapy involves collection of lymphocytes from the patient, T cell transfection with CAR, expansion and re-infusion. CAR is a monoclonal antibody that can target different antigens in tumour cells. Among them, CAR T cell that target CD19 in B cells has been successful in the treatment of acute lymphoblastic leukaemia and B cell lymphoma.
Vaccination Therapy
Vaccination therapy can aim to prevent the occurrence of cancer by reducing viral infections directly linked to malignancies. As examples, we can highlight the human papillomavirus vaccine to prevent cervical cancer and the hepatitis B vaccine to prevent liver cancer. However, most vaccines are therapeutic, using peptides derived from tumour antigens or DNA/RNA of cancer cells.
Oncolytic viral vaccines have recently been introduced and use viruses that selectively target tumour cells, by activation of dendritic cells and cross presentation of tumour antigens to T cells. Examples include Talimogene laherparepvec (T-VEC), a herpes simplex virus, engineered to express granulocyte-macrophage colony-stimulating factor (GM-CSF), increasing dendritic cell maturation.
Human and murine induced pluripotent stem cells (iPSC), modified to express tumour antigens may be used as therapeutic vaccines, because they can induce an antigen-specific T cell response.
Finally, dendritic cell vaccines that are exposed to tumour peptides/DNA/RNA are used as vaccines and several are currently undergoing clinical trials. Sipuleucel-T, a dendritic cell vaccine derived from patient blood and pulsed with a protein of prostatic acid phosphatase (PAP) and GM-CSF, has been approved to treat prostate cancer patients. A summary of the immunotherapy approaches and their known advantages/disadvantages is presented in the table below.
Conclusion
In conclusion, the identification and revision of the hallmarks of cancer has proved invaluable in our understanding of the development of malignancies and provided a framework for scientists around the world to research different pathways of tumorigenesis, eventually leading to our current knowledge.
The addition of the final two hallmarks, particularly the ability of cancer cells to avoid immune detection reflects the advances in scientific research and allowed for explanations to be formulated, addressing key aspects of cancer cells that seemed a paradox, such as the knowledge that tumour cells have antigens identified as non-self but ultimately this had little impact in preventing the development of malignancies in individuals with functioning immune systems. The concept of immunoediting overcame these shortages and provided some clarity on the mechanisms that tumour cells use to avoid immune destruction.
Our growing knowledge of tumour cells and how they overcome immune detection and destruction meant that targeted therapies can be designed and trialled, in order to complement the more established therapies, such as surgery and chemotherapy. Cancer immunotherapy appears as a precision therapy, targeting cancer cells and sparing healthy cells, with great potential in terms of reducing the side effects of traditional chemotherapy, which is less specific. Several types of cancer immunotherapy are currently undergoing clinical trials and, in the future, it will be interesting to see the advances in this field, hopefully leading to a more targeted approach, high success rates in treating different cancers and the ability to reduce the burden that traditional therapies inflict in healthcare systems and patients alike.
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