Cancer cells and their ability to avoid the immune system

Since cancer cell retain their ability to trigger the immune system from their pre-cancerous state and any condition that causes an auto-immune reaction in a specific area of the body will attack any cells in that area then could an auto-immune reaction actually attack any cancer cells in that area also?

Noting that regular human cells are not able to avoid 'attacks' by an auto-immune response so the normal cells can not pass on any 'strategies' for avoiding an auto-immune disease attack to any cancerous cells they 'turn into'… Is all this possible?

There are several types of cancer immune evasion. Such as releasing immunesupressive cytokines, downregulation of MCH and comprising mutiations which are not immunogenic. If the cancer at a tissue is evading immune system by immunosupressive cytokines it may not be affected from auto-immune attack. However if the cancer is not attacked by the immune system just because it is not "different" enough from the nearby healthy tissues, then at this time auto-immune attack to the tissue may technnically attack the cancer also.

Mostly wrong, yet not a bad notion.

Most* (*all? Been too long.) forms of cancers turn off the natural identification scheme (self-MHC or major histocompatibility complex) as well as the limits on replication. This is because there is a self-kill switch attached to that system.

A cancer would need to release the stand-down signal in a timely fashion, which it cannot do if it is spending its resources on rapid growth.

This means most* cancers are already valid targets without needing an auto immune disorder.

At least one targeted anti-cancer treatment operates by turning MHC back on, causing them to die.

There may be some sorts where the ability to target native cells would help. Doubt it, but could be.

Cancer cells cooperate to fight off the immune system and overcome therapy

Images captured from video show movement of cytotoxic T cells (red) monitoring melanoma tumor cells (green) in vivo. Photo by Shuyin Li, Gajewski lab.

Immunotherapy research has a long history at the University of Chicago Medicine Comprehensive Cancer Center, dating back to the work of Dr. Frank Fitch in the late 1980s that demonstrated the potent ability of T cells to reject a deadly tumor type. Researchers at the Comprehensive Cancer Center were early to understand the concept that many patients do mount a spontaneous immune response against tumors, but that the work is often not completed due to negative feedback mechanisms that turn off or dampen the immune response. These biological mechanisms are critical for controlling against auto-immunity but, unfortunately, these checks on the immune response help cancerous cells evade destruction.

One such mechanism is the expression of a protein called PD-1 on the surface of T cells. When bound by its ligand, PDL-1, T cells become inactivated, creating a major limit to the immune response. The ligand, PDL-1, is expressed on many cell types, and it is up-regulated following T cell activity. Cancer cells are able to hijack this method of T cell suppression by producing PD-L1 and directly turning off T cells. Although there are many pathways that inactivate T cells, the PD-1/PDL-1 mechanism is a dominant method that cancer cells use to directly disarm T cells.

Immune and Inflammatory Cells in Thyroid Cancer Microenvironment

A hallmark of cancer is the ability of tumor cells to avoid immune destruction. Activated immune cells in tumor microenvironment (TME) secrete proinflammatory cytokines and chemokines which foster the proliferation of tumor cells. Specific antigens expressed by cancer cells are recognized by the main actors of immune response that are involved in their elimination (immunosurveillance). By the recruitment of immunosuppressive cells, decreasing the tumor immunogenicity, or through other immunosuppressive mechanisms, tumors can impair the host immune cells within the TME and escape their surveillance. Within the TME, cells of the innate (e.g., macrophages, mast cells, neutrophils) and the adaptive (e.g., lymphocytes) immune responses are interconnected with epithelial cancer cells, fibroblasts, and endothelial cells via cytokines, chemokines, and adipocytokines. The molecular pattern of cytokines and chemokines has a key role and could explain the involvement of the immune system in tumor initiation and progression. Thyroid cancer-related inflammation is an important target for diagnostic procedures and novel therapeutic strategies. Anticancer immunotherapy, especially immune checkpoint inhibitors, unleashes the immune system and activates cytotoxic lymphocytes to kill cancer cells. A better knowledge of the molecular and immunological characteristics of TME will allow novel and more effective immunotherapeutic strategies in advanced thyroid cancer.

Keywords: anaplastic thyroid cancer differentiated thyroid cancer immune cells immune checkpoints macrophages mast cells neutrophils papillary thyroid cancer poorly differentiated thyroid cancer tumor microenvironment.

Conflict of interest statement

The authors declare no conflict of interest.


Dual role of immune cells…

Dual role of immune cells in thyroid cancer growth and progression. Tumor-infiltrating immune…

A schematic view of tumor-infiltrating…

A schematic view of tumor-infiltrating immune cells interactions among each other and with…

Cytokines and chemokines released in…

Cytokines and chemokines released in thyroid cancer microenvironment and their role in recruiting…

Discovery: Research at Princeton

When Daniel D. Liu first encountered the world of research, he saw giants in white lab coats shaking flasks and squirting liquids into small vials. He was 4 years old, and his parents, both biochemists, would bring him to work and set him down with a book and instructions to keep quiet.

“I didn’t really understand what was happening, but I guess that was my first impression of what adults do,” said Liu, Class of 2018, who is majoring in molecular biology. It was no wonder that he went into the family business at a young age. During summer breaks in high school, he worked at the National Institutes of Health near his home in Potomac, Maryland.

At Princeton, Liu joined the laboratory of Yibin Kang, the Warner-Lambert/Parke-Davis Professor of Molecular Biology, where he focuses on breast cancer stem cells, which are a subset of cancer cells that can self-renew and cause tumors to spread or grow back after treatment.

Undergraduate Daniel D. Liu co-authored a Nature Cell Biology study on the discovery of an RNA molecule that protects stem cells.

In a study published earlier this year in Nature Cell Biology, Liu helped identify a molecule that protects cancer stem cells by shielding them from the immune system. When the immune system cannot attack the cancer cells, the cells can spread to surrounding tissues, a process known as metastasis and a leading cause of cancer-related deaths.

The team found that when cells produce a lot of this molecule — actually a short strand of genetic information called microRNA-199a — both healthy and cancerous cells take on stem cell-like properties such as a heightened ability to regenerate breast tissue and to create spherical clumps of cells called mammospheres.

This stem cell-like property is necessary for normal breast tissue functioning, but it is also fuel for cancer cells to survive and duplicate, helping them to escape from the suppressive effects of immune cells.

The findings may shed light on the puzzle of why immunotherapy, a cancer treatment that spurs the immune system to attack tumors, is highly successful against some types of cancer patients but does not work well for others.

“Everyone is really banking on immunotherapy as a breakthrough in cancer treatment, but it only works really well for some types of cancers,” Kang said. “In breast cancer the response isn’t great, and we don’t really understand why.”

As a result of this study, made possible through funding from the National Institutes of Health and the U.S. Department of Defense, Kang now thinks the lack of response to immuno-therapy by some patients could, in part, be due to the microRNA’s role in protecting the cancer stem cells.

Since the team now understands what guards the cancer cells, Liu said, “perhaps we can target this pathway so as to sensitize cancer stem cells to immunotherapy.”

Liu’s contributions to the lab go beyond bench experiments. Recently, he coded a user-friendly program that enables the team to sift through large patient data sets quickly, improving upon the lab’s previous, manual approach. He also co-founded the Princeton Undergraduate Research Journal (see page 2) to help fellow students publish their work and learn firsthand about the peer-review process.

“Daniel not only does his own work but also makes life much easier for everyone in the lab,” Kang said. “It’s quite unusual for an undergraduate to make fundamental contributions to the lab that enable everyone to do research in a better way.”

About this research

A team of immunologists with the Centre for Immunology and Infection, part of the University of York&rsquos Department of Biology and Hull York Medical School, has presented new research on cancer immune checkpoints.

The team included Dr Dimitris Lagos a Senior Lecturer in Immunology, PhD student Daniel Yee, and Professor Mark Coles.

Presented in the Journal of Biological Chemistry, the research was carried out in collaboration with the Barts Cancer Institute, Queen Mary University of London.

The research was funded by the Medical Research Council (MR/L008505/1) and the Biotechnology and Biological Sciences Research Council (B/J01113/1 and BB/I007571/2).

University of York
YO10 5DD
United Kingdom
Tel: +44 (0) 1904 320 000

The cancer genes that disarm the immune system

The specific genes that let cancer cells skate past the defences of the immune system.

Mobilizing the forces of the immune system to the fight has changed the game of cancer treatment in recent years.

The key to success has been first identifying how cancer cells disarm the T-cell fighters of the immune system and then finding drugs to restore their firepower.

Using drugs called checkpoint inhibitors, patients with incurable cancers like advanced melanoma have shown long-term responses.

Forty percent of melanoma patients will still fail to respond to the treatment, however, which means that cancer cells must have other means – ones that are not addressed by checkpoint inhibitors – to disable the immune system’s weaponry.

To discover what they are, a research team led by Nicholas Restifo at the US National Cancer Institute began with human melanoma cells growing in a dish, and systematically disabled every gene in the melanoma cells using the CRISPR gene-editing technique.

They then tested the ability of the T-cells fighters to recognize each one. It turned out about 100 different genes activated by the cancer were able to prevent the attack by the T-cells.

Of particular interest was a gene called APLNR. While it has been implicated as contributing to some cancers, this was the first evidence that it played a role in disarming T-cells.

“If we can truly understand mechanisms of resistance to immunotherapy, we might be able to develop new therapeutics,” comments Restifo.

Elizabeth Finkel

Elizabeth Finkel is editor-at-large of Cosmos.

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Cancer cells have defects in the control mechanisms that govern how often they divide, and in the feedback systems that regulate these control mechanisms (i.e. defects in homeostasis).

Normal cells grow and divide, but have many controls on that growth. They only grow when stimulated by growth factors. If they are damaged, a molecular brake stops them from dividing until they are repaired. If they can't be repaired, they commit programmed cell death (apoptosis). They can only divide a limited number of times. They are part of a tissue structure, and remain where they belong. They need a blood supply to grow.

All these mechanisms must be overcome in order for a cell to develop into a cancer. Each mechanism is controlled by several proteins. A critical protein must malfunction in each of those mechanisms. These proteins become non-functional or malfunctioning when the DNA sequence of their genes is damaged through acquired or somatic mutations (mutations that are not inherited but occur after conception). This occurs in a series of steps, which Hanahan and Weinberg refer to as hallmarks.

Capability Simple analogy
Self-sufficiency in growth signals "accelerator pedal stuck on"
Insensitivity to anti-growth signals "brakes don't work"
Evading apoptosis won't die when the body normally would kill the defective cell
Limitless replicative potential infinite generations of descendants
Sustained angiogenesis telling the body to give it a blood supply
Tissue invasion and metastasis migrating and spreading to other organs and tissues

Self-sufficiency in growth signals Edit

Typically, cells of the body require hormones and other molecules that act as signals for them to grow and divide. Cancer cells, however, have the ability to grow without these external signals. There are multiple ways in which cancer cells can do this: by producing these signals themselves, known as autocrine signalling by permanently activating the signalling pathways that respond to these signals or by destroying 'off switches' that prevents excessive growth from these signals (negative feedback). In addition, cell division in normal, non-cancerous cells is tightly controlled. In cancer cells, these processes are deregulated because the proteins that control them are altered, leading to increased growth and cell division within the tumor. [4] [5]

Insensitivity to anti-growth signals Edit

To tightly control cell division, cells have processes within them that prevent cell growth and division. These processes are orchestrated by proteins known as tumor suppressor genes. These genes take information from the cell to ensure that it is ready to divide, and will halt division if not (when the DNA is damaged, for example). In cancer, these tumour suppressor proteins are altered so that they don't effectively prevent cell division, even when the cell has severe abnormalities. Another way cells prevent over-division is that normal cells will also stop dividing when the cells fill up the space they are in and touch other cells known as contact inhibition. Cancer cells do not have contact inhibition, and so will continue to grow and divide, regardless of their surroundings. [4] [6]

Evading programmed cell death Edit

Cells have the ability to 'self-destruct' a process known as apoptosis. This is required for organisms to grow and develop properly, for maintaining tissues of the body, and is also initiated when a cell is damaged or infected. Cancer cells, however, lose this ability even though cells may become grossly abnormal, they do not undergo apoptosis. The cancer cells may do this by altering the mechanisms that detect the damage or abnormalities. This means that proper signaling cannot occur, thus apoptosis cannot activate. They may also have defects in the downstream signaling itself, or the proteins involved in apoptosis, each of which will also prevent proper apoptosis. [4] [7]

Limitless replicative potential Edit

Cells of the body don't normally have the ability to divide indefinitely. They have a limited number of divisions before the cells become unable to divide (senescence), or die (crisis). The cause of these barriers is primarily due to the DNA at the end of chromosomes, known as telomeres. Telomeric DNA shortens with every cell division, until it becomes so short it activates senescence, so the cell stops dividing. Cancer cells bypass this barrier by manipulating enzymes (telomerase) to increase the length of telomeres. Thus, they can divide indefinitely, without initiating senescence. [4] [8]

Mammalian cells have an intrinsic program, the Hayflick limit, that limits their multiplication to about 60–70 doublings, at which point they reach a stage of senescence.

This limit can be overcome by disabling their pRB and p53 tumor suppressor proteins, which allows them to continue doubling until they reach a stage called crisis, with apoptosis, karyotypic disarray, and the occasional (10 −7 ) emergence of an immortalized cell that can double without limit. Most tumor cells are immortalized.

The counting device for cell doublings is the telomere, which decreases in size (loses nucleotides at the ends of chromosomes) during each cell cycle. About 85% of cancers upregulate telomerase to extend their telomeres and the remaining 15% use a method called the Alternative Lengthening of Telomeres. [9]

Sustained angiogenesis Edit

Normal tissues of the body have blood vessels running through them that deliver oxygen from the lungs. Cells must be close to the blood vessels to get enough oxygen for them to survive. New blood vessels are formed during the development of embryos, during wound repair and during the female reproductive cycle. An expanding tumour requires new blood vessels to deliver adequate oxygen to the cancer cells, and thus exploits these normal physiological processes for its benefit. To do this, the cancer cells acquire the ability to orchestrate production of new vasculature by activating the 'angiogenic switch'. In doing so, they control non-cancerous cells that are present in the tumor that can form blood vessels by reducing the production of factors that inhibit blood vessel production, and increasing the production of factors that promote blood vessel formation. [4] [10]

Tissue invasion and metastasis Edit

One of the most well known properties of cancer cells is their ability to invade neighboring tissues. It is what dictates whether the tumor is benign or malignant, and is the property which enables their dissemination around the body. The cancer cells have to undergo a multitude of changes in order for them to acquire the ability to metastasize, in a multistep process that starts with local invasion of the cells into the surrounding tissues. They then have to invade blood vessels, survive in the harsh environment of the circulatory system, exit this system and then start dividing in the new tissue. [4] [11]

In his 2010 NCRI conference talk, Hanahan proposed two new emerging hallmarks and two enabling characteristics. These were later codified in an updated review article entitled "Hallmarks of cancer: the next generation." [2]

Emerging Hallmarks Edit

Deregulated metabolism Edit

Most cancer cells use alternative metabolic pathways to generate energy, a fact appreciated since the early twentieth century with the postulation of the Warburg hypothesis, [12] [13] but only now gaining renewed research interest. [14] Cancer cells exhibiting the Warburg effect upregulate glycolysis and lactic acid fermentation in the cytosol and prevent mitochondria from completing normal aerobic respiration (oxidation of pyruvate, the citric acid cycle, and the electron transport chain). Instead of completely oxidizing glucose to produce as much ATP as possible, cancer cells would rather convert pyruvate into the building blocks for more cells. In fact, the low ATP:ADP ratio caused by this effect likely contributes to the deactivation of mitochondria. Mitochondrial membrane potential is hyperpolarized to prevent voltage-sensitive permeability transition pores (PTP) from triggering of apoptosis. [15] [16]

The ketogenic diet is being investigated as an adjuvant therapy for some cancers, [17] [18] [19] including glioma, [20] [21] because of cancer's inefficiency in metabolizing ketone bodies.

Evading the immune system Edit

Despite cancer cells causing increased inflammation and angiogenesis, they also appear to be able to avoid interaction with the body's immune system via a loss of interleukin-33. (See cancer immunology)

Enabling Characteristics Edit

The updated paper also identified two emerging characteristics. These are labeled as such since their acquisition leads to the development of the hypothesized "hallmarks"

Genome instability Edit

Cancer cells generally have severe chromosomal abnormalities which worsen as the disease progresses. HeLa cells, for example, are extremely prolific and have tetraploidy 12, trisomy 6, 8, and 17, and a modal chromosome number of 82 (rather than the normal diploid number of 46). [22] Small genetic mutations are most likely what begin tumorigenesis, but once cells begin the breakage-fusion-bridge (BFB) cycle, they are able to mutate at much faster rates. (See genome instability)

Inflammation Edit

Recent discoveries have highlighted the role of local chronic inflammation in inducing many types of cancer. Inflammation leads to angiogenesis and more of an immune response. The degradation of extracellular matrix necessary to form new blood vessels increases the odds of metastasis. (See inflammation in cancer)

An article in Nature Reviews Cancer in 2010 pointed out that five of the 'hallmarks' were also characteristic of benign tumours. [23] The only hallmark of malignant disease was its ability to invade and metastasize. [23]

An article in the Journal of Biosciences in 2013 argued that original data for most of these hallmarks is lacking. [24] It argued that cancer is a tissue-level disease and these cellular-level hallmarks are misleading.

The cancer-natural killer cell immunity cycle

Immunotherapy with checkpoint blockade induces rapid and durable immune control of cancer in some patients and has driven a monumental shift in cancer treatment. Neoantigen-specific CD8 + T cells are at the forefront of current immunotherapy strategies, and the majority of drug discovery and clinical trials revolve around further harnessing these immune effectors. Yet the immune system contains a diverse range of antitumour effector cells, and these must function in a coordinated and synergistic manner to overcome the immune-evasion mechanisms used by tumours and achieve complete control with tumour eradication. A key antitumour effector is the natural killer (NK) cells, cytotoxic innate lymphocytes present at high frequency in the circulatory system and identified by their exquisite ability to spontaneously detect and lyse transformed or stressed cells. Emerging data show a role for intratumoural NK cells in driving immunotherapy response and, accordingly, there have been renewed efforts to further elucidate and target the pathways controlling NK cell antitumour function. In this Review, we discuss recent clinical evidence that NK cells are a key immune constituent in the protective antitumour immune response and highlight the major stages of the cancer-NK cell immunity cycle. We also perform a new analysis of publicly available transcriptomic data to provide an overview of the prognostic value of NK cell gene expression in 25 tumour types. Furthermore, we discuss how the role of NK cells evolves with tumour progression, presenting new opportunities to target NK cell function to enhance cancer immunotherapy response rates across a more diverse range of cancers.

Killing cancer softly: New approach halts tumor growth

One of the reasons that cancer is so hard to beat is the way that it ropes our immune system into working against us. Treatment kills off some cancer cells, but what’s left behind can “trick” our immune system into helping tumors to form. New research may have found a way to break this vicious circle.

Share on Pinterest Sometimes our immune system helps cancer cells (shown here) to spread.

In what has been referred to as the “ tumor growth paradox ,” killing off cancer cells can sometimes cause more cancer cells to spread.

This occurs because the cellular debris that is left behind triggers an inflammatory response from our immune system, which, in turn, can stimulate the production of more cancer cells.

But researchers may now have found a way out of this conundrum. A new study has found that resolvins — compounds naturally secreted by our body in order to stop the inflammatory response — can stop tumors from growing when such growth is induced by cellular waste.

The research was led by Sui Huang, from the Institute of Systems Biology in Seattle, WA, as well as Charles N. Serhan, from the Brigham and Women’s Hospital at Harvard Medical School, Mark Kieran, from the Dana-Farber Cancer Institute, and Dipak Panigrahy, from the Beth Israel Deaconess Medical Center, all of which are in Boston, MA.

Megan Sulciner is the first author of the paper, and the findings were published in The Journal of Experimental Medicine.

Sulciner and her colleagues used cytotoxic treatment and other targeted drugs to kill off laboratory-cultured cancer cells. The resulting cellular debris was injected into mice. The rodents already had a few cancer cells in them, but these were not enough to promote tumor growth on their own.

The researchers also treated mice with traditional chemotherapy drugs.

Both approaches stimulated the spread of cancer cells and boosted their ability to grow tumors. Debris-induced tumor growth could be seen both in vivo and in the cultured cells.

The study revealed that a lipid called phosphatidylserine — which is found on the surface of dead and stressed cells — makes the immune cells release pro-inflammatory cytokines.

The lead study authors spoke to Medical News Today about their findings and the mechanisms underlying them.

“Our studies,” they explained, “along with others, show that traditional cancer therapy may be a ‘double-edged sword,’ wherein the very treatment used to cure cancer is also helping it survive and grow.”

Although aimed at killing cancer cells, these therapies leave behind “tumor cell debris,” which, the researchers explained, “generates a ‘cytokine storm’ of pro-inflammatory pro-tumorigenic cytokines.”

The few cancer cells that do survive treatment, “combined with an inflammatory setting induced by tumor cell debris, may result in the ‘perfect storm’ for cancer progression. Therefore, conventional chemotherapy […] may contribute to tumor relapse,” explained the authors.

“The findings underscore the old idea that killing cancer cells with more and more effective drugs may backfire,” added Huang.

“The tumor tissue is a reactive system that turns cell-killing therapy into double-edge[d] swords: the more you kill the more you may stimulate the surviving tumor cells,” he added.

Huang explained, “Dead-cell stimulated growth is naturally a part of the tissue regeneration cycle debris is interpreted by the tissue as injury signal and stimulates wound healing and regeneration.”

“Whether a cytotoxic treatment is successful or not,” he added, “hinges on hitting a small window of opportunity: when the net kill effect is stronger than the stimulatory of the dead cells that treatment creates.”

The study’s lead authors said:

“ Overcoming the dilemma of debris-induced tumor progression is paramount if we are to prevent tumor recurrence of treatment-resistant tumors — the major reason for [the] failure of cancer therapy.”