By Sailesh Gunaseelan
Published 2:44 EST, Sun October 31st, 2021
Sailesh Gunaseelan
Abstract
The human immune system does a remarkable job protecting us from foreign invaders, such as viruses and bacteria [13][14]. Over the last decade, the field of cancer immunology has made tremendous progress in elucidating the relationship between the immune system and cancer cells [15][37]. Research has shown that cancer cells can effectively “hide” themselves from the immune system allowing them to grow unperturbed [28]. Proteins expressed on the cell membrane of cancer cells serve as “stop” signals for our immune system preventing immune cells from killing cancer cells [28]. This discovery has enabled scientists to create a new class of drugs called immunotherapeutic, which block these “stop” signals from the cancer cell, thereby allowing our immune system to selectively find and kill cancer cells[15][16][37][41]. While chemotherapy kills cancer cells and healthy cells causing widespread damage to cancer patients, immunotherapeutics not only acts as an effective treatment but also causes less damage to the patient [24]. Immunotherapy is the future for cancer treatment and holds significant promise in taking us towards a cure for cancer [30][33][37]. This review paper will describe how the human body’s immune system works, how cancer evades our immune system, and how immunotherapy restores the immune system’s function.
1. Introduction
1.1 – What Is Cancer?
Cancer is arguably the most frightening disease to be diagnosed and despite its long-standing presence in human history, society continues to race towards the perfect treatment. Data from 2017 showed that almost 10 million people died from cancer, and it is estimated that approximately 2 million people will be diagnosed with cancer in 2021 [8][29]. Though cancer occurrences are rare, it is the second-largest global killer of humans right below cardiovascular disease [29]. Due to its prevalence and deadly impact, cancer is an exceedingly pressing issue.
Figure 1: Causes of Death 2017: Cancer was the second-highest cause of death https://ourworldindata.org/cancer
1.2 – Origin
While viruses and bacteria are foreign organisms to the host, cancer cells are unique in the sense that they originate from healthy cells in the body [28]. There are countless ways in which cancer cells can be formed, but there is an overarching theme to their genesis, which begins with the cell cycle [6]. The cell cycle is the process by which cells reproduce through cell division [6]. There are four stages in the cell cycle: G1, DNA Synthesis, G2, and mitosis [6]. The most important stage in the development of cancer is DNA synthesis [6][40]. Healthy cells create two copies of identical, healthy DNA after DNA synthesis, but sometimes there is an error made during DNA synthesis which can mutate or “break” the DNA being synthesized [6][40]. Once DNA mutates up to a certain point, it can lose the ability to perform essential functions such as telling cells when to stop dividing [40]. When this happens, cancer cells form [40]. Cancer cells are cells that lose the ability to stop dividing [40]. As a result, cells become malignant and begin to spread throughout the body [40]. In fact, the term “cancer” acts as a placeholder, indicating various types of uncontrolled cell growth [40]. This occurs because the gene, a specific part of our DNA, which would normally tell cells to stop dividing has mutated and lost its ability to do so [6][40]. Cancer diagnoses have different stages of severity [31]. If the cancer is localized to one part of the body,
The odds of surviving are much better than if the cancer has spread out to other parts of the body [40]. Ultimately, to effectively treat cancer, it must be stopped at every stage.
1.3. – Types Of Cancer
Cancer is not a single disease because cancer cells can arise in different parts of the body [8][29]. Moreover, different cancers have different survival rates [4][7][8][23][32]. For instance, melanoma is the abnormal growth of skin cells, and glioblastoma is the growth of abnormal brain cells [19][27]. Glioblastoma is one of the deadliest types of cancer, with most patients dying within 2 years of diagnosis [27]. Melanoma, if caught early enough, can have survival rates as high as 100%, simply because the cancerous cells can be cut out before they begin to cause serious problems [19]. In addition, patients with common cancers (e.g., breast, skin, prostate, etc.) are known to have a higher chance of survival [4][5][8][23][39] and this is mainly due to doctors’ increased familiarity with these types of cancer, as well as the advancement of equipment and technology used to fight these diseases [11]. However, some cancers are far more lethal. In fact, Karen Selby from The Mesothelioma Center states, “According to the American Society, lung cancer – and lung cancer caused by asbestos – is the number one killer, with 142,670 estimated deaths in 2019 alone…” Lung, tracheal, and bronchial cancer have claimed the highest number of lives, with a devastating “1.9 million in 2017” (Our World In Data) [29].
1.4 – Risk Factors
Getting cancer can be due to poor genes, an unhealthy lifestyle, or bad luck [10][22][25]. If mutated genes are passed down from parent to child, the likelihood of having cancer increases [22][25]. If one smokes, drinks, and has poor eating habits, they can introduce mutations to the body which can mutate the DNA and cause cancer [7][10][22][25]. Smoking, for example, introduces a significant number of mutagens to the body which mutates the DNA and causes extreme damage to cells, making them cancerous [25]. Lastly, a random error made during DNA synthesis can be enough to cause cancer [10][25]. Although the last cause is very rare, it can happen.
2 – Current Research
2.1 – Treatments
Given the deadly nature of cancer, there has been a lot of research into diagnosing and treating cancer. In order to determine the presence of cancer, various methods such as physical exams, laboratory tests, imaging tests, and biopsy are used [21]. When a patient has been diagnosed with cancer, a doctor can proceed in various ways, based on the threat level and current stage [21]. Depending on the type of cancer, doctors can select the correct treatment in order to handle the disease [21]. This may include curative, primary, adjuvant, and palliative treatment [21]. A cure occurs when the doctor removes any possibility of cancer cells returning, allowing the patient to live a normal life [21]. Such a treatment is highly unlikely with cancer and depends heavily on the patient’s circumstances [21]. A much more practical treatment would be the primary treatment, wherein the doctor removes all cancer cells from the patient’s body, typically by surgery [21]. However, even when cancer cells are removed, there is a high chance of cancer continuing to grow, underlining the importance of adjuvant treatment [21]. Adjuvant treatment is an attempt to exterminate any cancer cells that reappear. [21]. In some cases, there are also times where it is not possible to terminate the cancer cell’s growth [21]. During these times, the most effective treatment is a palliative treatment, which focuses on alleviating a patient’s symptoms when remission is not possible [21].
2.2 – Chemotherapy
One of the most common treatments for cancer is chemotherapy [20][36][38]. Chemotherapy consists of the implementation of various drugs, used to prevent cancer cells from growing and dividing [20][36][38]. The treatment is most effective after the formation of large tumors that have begun to spread rapidly and cannot be effectively removed through surgery [20][36][38]. While radiation and surgery target specific areas of the body, chemotherapy can treat the entire body [20][36][38]. Unfortunately, chemotherapy has major side effects [20][38]. As chemotherapy drugs work their way through the body, they can affect other fast-growing healthy cells, which include the skin, hair, intestines, and bone marrow [20][36][38]. Due to the potential for major complications, chemotherapy is not a perfect treatment, which is why scientists have been furiously working in order to create new ways of treating cancer.
Figure 2: Effects of Chemotherapy on the human body
https://www.medicalnewstoday.com/articles/323485
3. Cancer Immunology
3.1 – The Immune System
The human immune system helps to fight off invaders, such as viruses and bacteria, in the body [13][14]. However, cancer is often able to grow uncontrolled and unperturbed by our immune system [28]. A common cold can be healed in a matter of days with little to no medicine, as our immune system eradicates the virus from our bodies [13][14]. However, with cancer, medicines like chemotherapy and radiation treatment are almost always necessary to eradicate cancer cells [21]. To understand why the body is often unable to fight cancer cells, it is important to understand how the human immune system works.
The immune system is an umbrella term for a set of specialized cells that defend the human body against viruses, bacteria, and fungi [34]. Humans have two types of responses to any foreign invader: innate and adaptive [34]. The innate response is the first response from the immune system [34]. It is what causes the redness and inflammation associated with cuts on the skin, and it is responsible for the first round of destruction of foreign invaders [34]. The adaptive response is a more specialized and coordinated defense against foreign invaders [34]. It’s responsible for identifying previously fought infections like viruses and producing neutralizing molecules, called antibodies, that are mobilized against previously fought infections [34].
3.2 – Organs of The Immune System
Each of the body’s systems has specialized organs and cells, and the immune system is no different. Much like how the cardiovascular system is composed of the heart, veins, and arteries, the immune system also comes with a specialized set of organs [13][14][35]. Bone marrow, thymus, tonsils, spleen, and lymph nodes are hubs where immune cells are born, matured, and kept in reserve until they are needed to fight off foreign invaders [13][14][35]. Moreover, the human body comes equipped with an external barrier, making it difficult for viruses, bacteria, and fungi to harm the skin [13][14][35]. The best way of fighting germs is to make sure they do not enter the body in the first place. The skin is the first line of defense against germs, but if the skin gets cut, there are immune cells lying in wait underneath the surface ready to attack whatever comes in [13][14][35]. Moreover, certain reflexes like coughing and sneezing help the body expel germs that may be trying to get into the airways [13][14][35].
Figure 3: Parts of The Immune System – Location of the various organs in the immune system https://www.ncbi.nlm.nih.gov/books/NBK279395/
3.3 – Immune Cells
The immune system also comes with its own specialized set of cells [13][26]. These include cells such as lymphocytes, neutrophils, and macrophages [13][26]. Lymphocytes are cells that take part in the adaptive immune response and help the body fight off viruses [13]. These cells originate in the bone marrow [13]. Some move to the thymus where they mature further and become T-cells, whereas others stay in the bone marrow and become B-cells [13][42]. T-Cells can be considered as the United States Marines: they need to be called upon to a site of danger, they kill selectively while leaving non-intruders unharmed and they inform other members of the group of the invaders they attacked and what the invaders look like [13][26][42]. T-cells effectively search and destroy whatever is not supposed to be in the body [13][26][42]. B-cells act like the FBI of the immune
system [2][13][26][42]. They keep a record of invaders the body has fought off and they deploy specialized molecules called antibodies to help neutralize invaders and help alert T-cells to a site of danger [2][13][26][42]. Neutrophils and macrophages are a part of the innate immune system [13][26][42]. They are both responsible for engulfing foreign invaders like bacteria and small microbes and preventing them from causing mass havoc in the body [13][26][42]. If the innate response is not sufficient to get rid of invaders, then an adaptive response arrives in order to act upon the virus [13][26][42].
3.4 – Receptors and Ligands
Communication is extremely important for immune cells [17][18]. Immune cells need to be able to communicate with one another about potential invaders and the actions they take against them [17][18]. Cells communicate with each other through molecules known as receptors and ligands [17]. Receptors are proteins that generally reside on the outer membrane of cells exposed to the environment and ligands are the molecules which attach to their host receptor much like a lock and key mechanism [9][17]. There is one key (a ligand) for a lock (a receptor) [17]. Immune cells “know” what to do depending on which ligand and receptor come into contact. If the ligand is unfamiliar to the immune cell, the immune cell knows that it is a foreign ligand and the cell expressing this foreign material must be destroyed because it may be harmful to the body [17]. Receptor-ligand interactions can be stimulatory, meaning they can stimulate immune cells to go out and attack invaders, or they can be immunosuppressive, meaning they can “turn off” an immune response [9][17]. To properly regulate our immune response, healthy cells must express immunosuppressive ligands so that the body’s immune system does not attack itself, and foreign invaders express stimulatory ligands that prompt the immune system to attack [17].
Receptors are crucial for immune cells to determine the difference between both an unhealthy and healthy cell [17]. Ligands known as non-self-antigens (bacteria/fungi) trigger the immune response, resulting in the invader being attacked [17]. It’s extremely important for the immune system to be able to identify the difference, as unhealthy cells are detrimental to an individual’s health, while healthy cells allow the body to function correctly [17].
Figure 4: Overview of The Immune System-Reaction of the Killer T-Cell after recognizing a healthy and infected cell (receptor + antigen)
3.5 – Cancer Hiding from The Immune System
Although the immune system can protect us from foreign invaders, it seemingly has trouble protecting us from cancer cells [28]. Healthy cells in our bodies know all the neat tricks our bodies use to protect themselves from the immune system [28]. Cancer cells, developed from once healthy cells, maintain their knowledge of how to hide from the immune system [28]. This evasion from the immune system allows cancer cells to grow virtually undisturbed in the human body [28]. Cells in our bodies use receptors and ligands to communicate with the immune system [28]. One “hiding” mechanism cancer cells use is the PD-1/PD-L1 axis [28]. PD1 (programmed death 1), is a receptor found on T-cells [28]. PD-L1 (programmed-death ligand 1) is a ligand found on many healthy cells in human bodies (such as placenta cells) as well as cancer cells [28]. When PD L1 and PD-1 come into contact, the T-cells that express PD-1 are essentially “turned off.” [28].
Figure 5: PDL1(green) and PD1(orange) interact with each other to modulate immune responses https://www.rcsb.org/structure/3BIK
When PD-L1 expressed by cancer cells encounter PD-1 expressed by T-cells, the cancer cells effectively “turn off” and prevent the T-cells from attacking them [28]. This process is incredibly effective in preventing an immune response and has been a source of drug-discovery efforts [28]. If this process can prevent T-cells from attacking cancer cells, then this can be drugged and allow the immune system to attack cancer cells [28].
Figure 6: Cancer Cells Preventing the Immune Response – Reaction of cancer cells, passing the immune system checkpoint using the PDL1 pathway
4. Immunotherapy
4.1 – What Is Immunotherapy
Recent research and clinical success have shown that our bodies are best for fighting cancer [15][16][37][41]. Immunotherapy has made remarkable progress in the last decade, showing a great deal of promise for the future [15][16][37][41]. According to the CRI (Cancer Research Institute), “Cancer immunotherapy, also known as immuno-oncology, is a form of cancer treatment that uses the power of the body’s own immune system to prevent, control, and eliminate cancer [41].” In simpler terms, immunotherapy allows the immune system to attack cancer cells, using additional help from outside sources [15][16][37][41]. An example mentioned before consisted of the PD1 pathway, with the cancer cell emitting PDL1, allowing it to evade the PD1 receptor from the Killer T-Cell [15][16][37][41]. With immunotherapy, it is possible to block the PD1 receptor, leaving the cancer cell defenseless against the Killer T-cell [15][16][37][41]. The treatment can come in various forms, such as antibodies, cancer vaccines, adoptive cell transfer, tumor-infecting viruses, checkpoint inhibitors, cytokines, and adjuvants [15][16][37][41]. This treatment is also known as a form of biotherapy (BRM therapy) [15][16][37][41]. Genetic engineering, known as gene therapies, may also be used to support the fighting capabilities of
immune cells [37][41]. Immunotherapy is the science of using our immune system to treat diseases [37][41].
Figure 7: Drugs Blocking Receptor and T-Cell Killing Cancer Cells –As a result of the drug blocking the PD1 pathway, the Killer T-Cell can release its molecules, attacking the cancer cell
Figure 8: Anti-PD1 antibody immunotherapy (purple and green) binding to PD-1 (gold) – Immunotherapeutic agents act as pseudo-ligands and prevent real ligands from binding to their receptors of choice. Anti-PD1 physically blocks PD-L1 from binding to PD-1 thereby instigating an immune response against cancer cells
https://www.rcsb.org/3d-view/5B8C/1
4.2 – Immunotherapy vs. Chemotherapy
Though advancements have been made in chemotherapy, it is important to know the differences between immunotherapy and chemotherapy. Chemotherapy acts mainly indiscriminately killing both cancer cells and healthy cells [1][24]. Moreover, there is a possibility of the cancer cells returning later which may result in multiple rounds of treatment [1][24]. Immunotherapy, on the other hand, allows the immune system to selectively kill cancer cells while leaving non-cancerous cells intact–for the most part [1][24]. This means that our immune system is monitoring our bodies 24/7 to search and destroy newly arising cancer cells [1][24], whereas Chemotherapy focuses on cells that rapidly divide, targeting both cancerous and non-cancerous cells, leading to loss of skin cells, hair, and bone marrow cells. Immunotherapy generally comes with much milder side effects [1][24]. Common side effects include skin irritation around the injection site, fever/chills, rashes, and diarrhea [1][24]. As with all medicines, it is ultimately up to the physician to decide what is in the best interest of the patient’s health [1][24]. Given the type of cancer, its severity, and the patient’s biology, one form of treatment may be better than the other [1][24].
4.3 – Future of Immunotherapy
Immunotherapy has already been approved in the United States as well as all around the world in order to treat a variety of cancers [16]. As scientists and doctors continue to realize the prominence of immunotherapy, strong advances continue to be made in the field [16]. The CRI (Cancer Research Institute) states, “As of June 2017, the U.S. Food and Drug Administration (FDA) has approved 32 different immunotherapies for patients with cancers…” [16] Thirty-two
drugs have already been approved, showing how much the field of oncology has invested in this treatment [16]. Immunotherapy is typically used with other treatments (e.g., chemotherapy/radiation therapy). As research on the treatment has only recently started, doctors, as well as patients, do not consider it as the primary option [33]. In fact, doctors typically suggest the treatment only after other curative treatments have been exhausted. Bob Tedeschi from STAT
(American health-oriented news website) explains that “Immunotherapies work for only around 15 to 20 percent of cancer patients who receive them”, which is partly the reason why they are not prescribed at first [33]. Immunotherapy has a lot of potential, yet at its current stage, it can only benefit a small percentage of patients. However, scientists are still determined to make improvements to the treatment [33]. The current focus in immunotherapy research is moving immune cells to the exact location of cancer cells so that immunotherapy can function more effectively [30]. This treatment shows a lot of potential, yet more studies must be done for it to benefit thousands of lives that are impacted by cancer [30]. It is important for patients to determine with their oncologist which treatment is the best option for them [16][33]. However, with the incredible advances already shown, it’s natural to expect the prominence of immunotherapeutic in the future [30][33].
5. Conclusion:
Cancer is one of the many hallmarks of the human experience. Chances are that each of us knows or has heard of someone who has died from this disease. Given the medical advancements and a higher level of public awareness, we are now able to diagnose cancer early thereby increasing the survival rate of many people [4][8][14][31]. However, some cancers do not display symptoms until they have become malignant and spread to the rest of the body [31][40]. Chemotherapy, once regarded as the only treatment for cancer, has begun to lose its spotlight given the success of tumor immunology and immunotherapy [15][16][37]. Immunotherapeutic drugs allow the body to kill cancer cells without harming healthy cells as well as keeping a lookout for any new cancer cells that may arise in the body [15][16][37]. Even in its infancy, immunotherapy has effectively treated a significant number of cancer patients [15][37]. Although much is yet to be known about immunotherapy and though it is not foolproof, it holds significant promise as a safe and effective treatment for all cancer types, bringing us closer to a cure.
6. Acknowledgements
I would like to thank Polygence for giving me this incredible opportunity, as well as my mentor Nooriel Banayan who always encouraged me and was with me through every step. Without the knowledge gained through countless lessons, this project wouldn’t have been possible. This paper is for anyone who is not up to date with the progress made in cancer treatments and focuses on immunotherapeutic as the future. The cover photo was from png find, https://www.pngfind.com/mpng/hiRoixi_human-body-transparent-background-transparent background-transparent-human/.
Sailesh Gunaseelan, Youth Medical Journal 2021
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Youth Medical Journal 