Why are haploid cancer cells not killed by immune system?

Why are haploid cancer cells not killed by immune system?

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I have seen haploid cancer cells (I think it was leukemia cells) in a lab.

Sperms and eggs are haploid but are not destroyed by the body because they are protected by other cells surrounding them.

My questions :

  • How are haploid and diploid cells differentiated by our immune system ?

  • Why are the haploid cancer cells not killed ? I know I could as well ask why any cancer cells are not killed but I want to know if there is anything specific about these cells ?

  • How are these cells generated ? (By meiosis ?!)

Now that I did some research on this, it seems to be a very rare condition of acute lymphoblastic leukemia (ALL), see this article:"Chromosomes and causation of human cancer and leukemia. XLVII. severe hypodiploidy and chromosome conglomerations in ALL.". This article ("Origin of near-haploidy in malignant hematopoietic cells.") hypothesizes that this might happen through gradual chromosome loss during cancer formation and that in the end one clone with a lower than normal number of chromosomes.

This seems connected to a much worse outcome of the cancer than for hyperdiploidies (more chromosomes than normal). See the "Atlas of Genetics and Cytogenetics in Oncology and Haematology". They also define why haploid (or near haploid means: Less than thirty chromosomes, down to 23 have been observed). This is not the normal haploidy found in germ cells. Se also "Isolation and Characterization of a Near-Haploid Human Cell Line".

Since these chromosomal changes occur inside the nucleus I think this is mostly invisible to the immune system - so there is probably no difference how these cells escape the immune system compared to other cancer cells. I think its possible that due to the chromosomal loss some proteins which control apoptosis are lost, so the cells escape this fate as well. Regarding the immune question, you can either start with the following articles or simply go over to Pubmed and choose some articles. In this field there is a lot of research going on.

If there are access problems, let me know.

The recent publication in pancreatic neuroendocrine cancer revealed about one third of patients have a half of the genome haploid. They sequenced 57 samples (WES) and defined a group of samples MEN1 mutant and +-12 haploid chromosomes. As expected the group had the worst prognosis.

Natural Killer Cells and Cancer Immunity

Natural killer cells are aggressive cells of the immune system that play an important role in fighting cancer as well as viral-infected cells. While T cells are also important in cancer, natural killer cells are the "first responders" that are on the scene before the T cells are summoned. Not yet in use with other immunotherapy drugs, researchers are looking at ways to harness the actions of natural killer cells as they have T cells.

NK cells are a type of lymphocyte, which in turn are one of the types of white blood cells in the body. It's thought that NK cells make up 10% or less of the white blood cells in the body.

Synthetic biology used to target cancer cells while sparing healthy tissue

Stanford researchers have developed synthetic proteins that can rewire cancer cells in a lab dish by co-opting critical disease-associated pathways.

(Top) some types of cancers are caused by mutated or overexpressed cell surface proteins that signal to the nucleus (green pathway) to drive uncontrolled growth and survival. (Bottom) Using an approach called RASER, the cancer-causing signals are redirected away from cell growth and survival and toward programmed cell death (orange pathway).
Michael Lin and Stuart Jantzen

Synthetic proteins engineered to recognize overly active biological pathways can kill cancer cells while sparing their healthy peers, according to a study by researchers at the Stanford University School of Medicine.

The customizable approach, which the researchers call RASER, relies on just two proteins: The first is activated in the presence of an “always on” growth signal often found in cancer cells, and the second carries out a researcher-programmed response, such as triggering the expression of genes involved in cell death.

Although the experiments were confined to cells grown in the laboratory, the researchers believe the results could lead to a new type of cancer therapy in which synthetic proteins deliver highly targeted and customizable treatments to sidestep the sometimes devastating side effects of current options.

“We’re effectively rewiring the cancer cells to bring about an outcome of our choosing,” said Michael Lin, MD, PhD, associate professor of neurobiology and of bioengineering. “We’ve always searched for a way to kill cancer cells but not normal cells. Cancer cells arise from faulty signals that allow them to grow inappropriately, so we’ve hacked into cancer cells to redirect these faulty signals to something useful.”

A paper describing the work was published May 2 in Science. Lin is the senior author. Former graduate student Hokyung Chung, PhD, is the lead author.

Signals from receptors

Many cancers rely on a series of signals that originate from proteins called receptors that span the membrane of the cell. These signaling cascades, or pathways, are used by healthy cells to grow in response to external cues, for example during development or recovery from injury. Often, however, these receptor proteins are mutated or overexpressed in cancer cells in ways that render the receptor protein “always on,” providing the cell with constant, unwarranted signals for growth. The researchers focused on two receptors, EGFR and HER2 — members of a family of receptors called the ErbB receptors — that often drive the growth of brain, lung and breast cancers. HER2, for example, is targeted by Herceptin in breast cancer.

Many common anti-cancer drugs, including Herceptin, work by blocking the cascade of signals triggered by receptor activation. Unfortunately, however, these drugs have no way to discriminate between cancerous cells, in which the pathway is always activated, and healthy cells going about their business as usual. That’s where Lin and his team come in.

“We haven’t had a drug that can tell the difference between a pathway signaling normally and one that is abnormally active,” Lin said. “We knew we needed a better strategy, a more rational way of treating cancer. But we’ve not had a way to do it until recently.”

Chung and her colleagues designed a synthetic protein consisting of two natural proteins fused together — one that binds to active ErbB receptors and another that cleaves a specific amino acid sequence. They then engineered a second protein that binds to the inner surface of the cell membrane and contains a customizable “cargo” sequence that can carry out specific actions in the cell. When the first protein binds to an active ErbB receptor, it cuts the second protein and releases the cargo into the interior of the cell.

“When the receptor protein is always on, as it is in cancer cells, the released cargo protein accumulates over time,” Chung said. “Eventually enough accumulates to have an effect on the cell. In this way, the system produces an effect only in cancer cells, and we can convert the always-on state of the receptor into different outcomes through the choice of cargo protein.”

After several rounds of tinkering, the team saw that their RASER system, which stands for “rewiring of aberrant signaling to effector release,” was highly specific for cancer cells dependent on ErbB receptor activity. For their first test they chose to use a protein involved in triggering cell death as the RASER cargo.

Killing only overactive cells

The team compared the RASER system to two therapies currently used for metastatic breast cancer — a chemotherapy regimen and a drug that blocks ErbB activity — on several types of cultured cells: breast and lung cancer cells in which the ErbB pathway was overly active breast cancer cells in which ErbB activity was normal and noncancerous breast and lung cell lines.

The researchers found that the traditional chemotherapy regimen of carboplatin and paclitaxel killed all the cells indiscriminately. The effect of the ErbB pathway inhibitor on the viability of the cells varied and did not reliably correlate with ErbB pathway activity levels. Only RASER specifically killed those cells in which the ErbB pathway was overly active while sparing those in which ErbB activity was normal.

While much work remains to be done to learn whether RASER is effective in human tumors, the researchers are excited about the possibilities of re-engineering the system to recognize other receptors mutated in cancers and swapping the cargos to achieve different outcomes. Challenges include learning how best to deliver synthetic proteins into tumors and understanding how the immune system might react to RASER. But Lin is optimistic.

“We have so much more information now about cancer genomics, signaling and how cancer cells interact with the immune system,” Lin said. “It’s finally becoming practical to combine this knowledge with synthetic biology approaches to tackle some of these pressing human health problems. RASER is both customizable and generalizable, and it allows us for the first time to selectively target cancer cells while sparing normal signaling pathways.”

Other Stanford authors of the study are graduate student Xinzhi Zou former undergraduate student Bryce Bajar postdoctoral scholar Veronica Brand, PhD research scientist Yunwen Huo, PhD Javier Alcudia, PhD, director of Stanford’s Neuroscience Gene Vector and Virus Core and James Ferrell, MD, PhD, professor of chemical and systems biology and of biochemistry.

The study was supported by the National Institutes of Health (grants P50GM107615 and 5R01GM098734), a Stanford graduate fellowship, the Ilju Foundation, the Burroughs Wellcome Foundation, a Damon Runyon-Rachleff Innovation award and an Alliance for Cancer Gene Therapy Young Investigator Award.

Stanford’s departments of Bioengineering and of Neurobiology also supported the work. The Department of Bioengineering is jointly managed by the School of Medicine and School of Engineering.

How immune cells can be controlled to kill cancer

By engineering cancer-killing T cells that can be manipulated noninvasively by remote control, researchers have added a potentially powerful feature to an already promising type of immunotherapy known as CAR T cell therapy.

Share on Pinterest A less invasive, more powerful treatment for cancer could be on the horizon.

A report on the study, led by the University of California, San Diego (UCSD), is due to be published in the Proceedings of the National Academy of Sciences.

Immunotherapy, a relatively new approach to fighting cancer, manipulates and strengthens the patient’s own immune system to eliminate tumors.

One type of immunotherapy that is emerging rapidly is chimeric antigen receptor T cell (CAR T cell) therapy.

In CAR T cell therapy, immune cells called T cells are taken from a person and genetically modified in the laboratory so that they can recognize and kill cancer cells more effectively. The engineered cells are then multiplied and put back into the person.

The genetically modified part of the T cell is the chimeric antigen receptor (CAR). It contains various synthetic elements, including one that can recognize unique features of tumor cells known as tumor-associated antigens, and another that activates the T cell to kill the target.

As new generations of CAR T cell therapy have been developed, the CAR has become increasingly sophisticated and acquired more features, including some that boost the anti-tumor power and persistence of the modified T cells.

Two CAR T cell therapies have recently been approved in the United States: one for the treatment of acute lymphoblastic leukemia in children, and another for the treatment of advanced lymphoma in adults.

However, there are now concerns surrounding whether this type of immunotherapy can be used effectively to treat cancers with solid tumors, such as those of the breast and colon.

One concern is whether or not the engineered T cells can be made powerful enough to overcome the resistance that the microenvironment inside a solid tumor has to immune responses.

Renier J. Brentjens, a medical oncologist and an early pioneer of CAR T cell therapy, says that what is needed is a “super T cell.”

He and his team at Memorial Sloan Kettering Cancer Center in New York City, NY, are working on a solution to the microenvironment resistance problem that they call an “armored CAR T cell.”

Another concern that poses a challenge to therapy developers is that the “non-specific targeting of CAR T cells against nonmalignant tissues can be life-threatening,” says Peter Yingxiao Wang, a bioengineering professor at UCSD and one of the senior investigators on the new study.

In their journal report, Prof. Wang and the rest of the study team describe how they added new features to CAR T cell therapy in which the T cells carry modules that can be manipulated to produce gene and cell changes through remotely controlled and noninvasive ultrasound.

They believe that the new features potentially make CAR T cell therapy more powerful at fighting cancer and less likely to produce adverse side effects.

They say that there is a “critical need” for tools that can work in this way, particularly when translating new experimental treatments into animals and humans.

The new approach is an example of mechanogenetics, which is a new field that manipulates mechanical properties at the level of cells to alter gene expression and cell functions.

The team engineered the CAR on the T cells to carry mechano-sensors loaded with microbubbles that vibrate when exposed to ultrasound waves.

The microbubbles activate a protein encoded by a gene called Piezo Type Mechanosensitive Ion Channel Component 1 (PIEZO1). The PIEZO1 protein is a “mechanically activated ion channel that links mechanical forces to biological signals.”

Once activated, the PIEZO1 channel allows calcium ions to enter the T cell. This action triggers a cascade of molecular reactions that switch on genes that help the T cell to recognize and kill cancer cells.

“This work,” Prof. Wang says, “could ultimately lead to an unprecedented precision and efficiency in CAR T cell immunotherapy against solid tumors, while minimizing off-tumor toxicities.”

“ CAR T cell therapy is becoming a paradigm-shifting therapeutic approach for cancer treatment.”

Prof. Peter Yingxiao Wang

How does cancer evade the immune system? New mechanism revealed

Cancer’s ability to elude our body’s immune system has long puzzled researchers. The latest study pinpoints one of cancer’s protective cloaks and investigates a way to remove it.

Share on Pinterest Cancer and its interaction with the immune system is a complex story.

Cancer cells are cells that have gone awry they both multiply unchecked and function incorrectly. Normally, cells that are faulty, dead, or dying are cleared away by the immune system.

Macrophages — a type of white blood cell — are largely responsible for the consumption and destruction of foreign invaders and errant cells.

Although macrophages normally carry out their attacks with ruthless efficiency, some cancer cells manage to evade their roaming gaze. How do cancer cells fly under the immune system’s radar?

In 2009, Dr. Irving Weissman, director of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine, published research that goes some way toward answering this question. They identified a “don’t eat me” signal on cancer cells.

Dr. Weissman demonstrated that particularly aggressive cancer cells express higher levels of CD47 — a transmembrane protein — on their cell surface. CD47 binds to a protein called SIRPalpha on the surface of macrophages, reducing their ability to attack and kill the cancer cells.

Studies in animals have shown that treatment with an anti-CD47 antibody significantly increases macrophages ability to kill cancer cells. In some mouse models of cancer, the treatment even led to a cure. Clinical trials are underway to gauge whether this approach will be as successful in humans.

Recently, Dr. Weissman’s team published another paper, outlining research that uncovers another “don’t eat me” signal. This time, the molecule in focus is a cell surface protein called major histocompatibility complex class 1 (MHC class 1).

The researchers found that tumors with higher levels of MHC class 1 on their cell surfaces are more resilient to anti-CD47 treatment.

Adaptive immunity forms the basis of immunological memory — once our immune system has responded to a specific pathogen, if it meets the same intruder again, it can mount a swift and specific response. MHC class 1 are an important part of this wing of the immune system.

MHC class 1 are found on the surfaces of most cells. They take portions of internal cellular proteins and display them on the cell’s surface, providing a snapshot of the cell’s health. If the cell’s protein flags are abnormal, T cells destroy it. This interaction between MHC class 1 and T cells has been well described, but how macrophages are involved was not fully understood.

The current study found that a protein — LILRB1 — on the surface of macrophages binds to a part of MHC class 1 on the surface of cancer cells. Once it has bound, it prevents the macrophage from consuming and killing the cell. This response was seen both in a laboratory dish and in mice with human tumors.

By inhibiting the CD47-mediated pathway and the LILRB1 pathway, interfering with both “don’t eat me” signals, tumor growth was significantly slowed in mice. The results are published this week in Nature Immunology.

“ Simultaneously blocking both these pathways in mice resulted in the infiltration of the tumor with many types of immune cells and significantly promoted tumor clearance, resulting in smaller tumors overall.”

Amira Barkal, graduate student, joint lead author

Barkal continues, “We are excited about the possibility of a double- or perhaps even triple-pronged therapy in humans in which we combine multiple blockades to cancer growth.”

Immunotherapy for cancer is a rapidly developing field, but the story is a complex one. Different cancers have different immunological fingerprints for instance, some human cancer cells reduce the levels of MHC class 1 on their cell surface, helping them to evade T cells.

Individuals with these cancers might not respond particularly well to therapies designed to enhance T cell activity. However, these cancers might be more vulnerable to an anti-CD47 approach. This also works the other way around, cancers with plentiful MHC class 1 might be less affected by anti-CD47 treatment.

Uncovering how cancer cells avoid cell death and understanding how these pathways might be overturned is a difficult but critical endeavor. This study marks another step toward teaching our immune system how to slow cancer’s march.

Stay on target

While there are still some question marks about what causes these immune cells to pick out cancerous cells, there's no shortage of evidence that they do so effectively. The researchers tested the immune cells against resting and dividing normal cells and got no response. MC.7.G5 didn't kill healthy cells that were stressed or damaged. So, there's no indication that the immune cells accidentally go off target and kill healthy cells.

The researchers also confirmed that the cancer-killing T cells are defined by the standard receptor that T cells normally use to recognize infected cells. They made a copy of this receptor's genes and inserted them into T cells from an unrelated individual. They also killed cancerous cells from at least two different sources.

Finally, the authors injected lymphoma cells into immune-compromised mice, then added the cancer-killing T cells. In control mice without the cancer-killing cells, the lymphoma took over the bone marrow, eventually accounting for about 80 percent of the cells there. With the cancer-killing cells injected at the same time, the bone marrow in the mice consistently had far fewer cancer cells (consistently less than 10 percent of the total cells). This indicates that the immune cells can help keep cancer in check but may not be able to consistently eradicate it.

Does that mean, as the BBC has claimed, that these cells "May treat all cancer"? Well, to begin with, the T cells were seemingly unable to eliminate cancer in mice. That's more significant than it seems, in that lots of potential treatments seem to work well in mice, but few ever advance to the point of clinical trials in humans, much less end up being used as treatments. This is a case when mouse assays are helpful for knowing what deserves a closer look but far from the last word on a topic.

Virus-Induced Immunopathology

A host clearly has numerous mechanisms to recognize and eliminate the viruses that it encounters. However, some viruses persist despite these mechanisms, and then the immune responses may become detrimental to the host and cause immune-mediated disease. When an antigen (virus) persists, pathologic changes and diseases result from different types of immunologic interactions, including immediate hypersensitivity, antibody-mediated immune complex syndrome, and tissue damage caused by cell-mediated effector cells and antibody plus complement. Of these mechanisms, the immune complex syndrome during viral infections has been studied most intensively. Two major complications of deposition of immune complexes are vascular damage and nephritis. Some viral diseases in which immune complexes have been demonstrated are hepatitis B, infectious mononucleosis, dengue hemorrhagic fever, and subacute sclerosing panencephalitis.

Cytotoxic T cells also mediate immunopathologic injury in murine models of human infections (i.e., infections with lymphocytic choriomeningitis virus and poxviruses). Both cytotoxic T cells and T cells responsible for delayed-type hypersensitivity have also been implicated in the pathology associated with influenza pneumonia and coxsackievirus myocarditis of mice. A delicate balance between the removal of infected cells that are the source of viral progeny and injury to vital cells probably exists for T cells as well as for the other host immune components.

Viruses may sometimes circumvent host defenses. An important factor that may impair the function of sensitized T lymphocytes is apparent from the observation that T cells activated by reaction with antigen or mitogen lose their normal resistance to many viruses. Therefore, these activated T lymphocytes develop the capacity to support the replication of viruses, leading to impairment of T lymphocyte function.


Complement component 5a receptor

Cluster of differentiation

Cytotoxic T lymphocyte-associated molecule

Chemokine (C-X-C motif) ligand

Mitogen-activated protein/Extracellular signal-regulated kinase

Major histocompatibility complex

Phosphatidylinositol-4,5-bisphosphate 3-kinase- AKT8 virus oncogene cellular homolog

Signal transducer and activator of transcription

Transforming growth factor beta

Vascular endothelial growth factor A

Keeping Cancer Drugs inside Cells

One way cancer cells resist treatment is by expelling cancer drugs. For example, healthy cells have proteins known as transporters that pump out toxic agents. One such group of proteins, called the ATP-binding cassette (ABC) transporters, expels some chemotherapy drugs, including doxorubicin, and some targeted therapies, like imatinib (Gleevec®).


The ABC transporter proteins (named ABCB1, ABCG2, ABCC1 and ABCC10), located on the cell membrane (black and green meshwork), pump cancer drugs (red bubbles) out of the cell interior.

Michael Gottesman, M.D., head of the multidrug resistance section of NCI's Center for Cancer Research, and his colleagues study how ABC transporters contribute to cancer drug resistance. More than 30 years ago, they discovered that "in some cases, when patients go from being sensitive to resistant to treatment, their cancer cells start to overexpress ABC transporters," he said.

In more recent studies, they analyzed DNA and RNA from tumors that are sensitive to or resistant to chemotherapy and found "increases in expression of one or more of these transporters in many different kinds of tumors," said Dr. Gottesman.

When given in combination with other cancer therapies, drugs that block the activity of ABC transporters might allow greater amounts of anticancer drugs to accumulate in cancer cells, thereby boosting their effect, he explained.

Earlier versions of ABC transporter inhibitors did not hit their intended molecular targets specifically and caused serious side effects. A later generation of inhibitors were better at blocking the activity of these transporters but were also very toxic in clinical trials. Toxicity likely stems from the fact that ABC transporters also serve important roles in healthy cells, Dr. Gottesman explained.

Now scientists are working to develop new ABC transporter inhibitors that, they hope, strike a balance between increased efficacy and decreased toxicity. For example, several independent groups have found that the drug osimertinib (Tagrisso®), originally developed as a tyrosine kinase inhibitor, can block ABC transporters and enhance the effect of chemotherapy drugs in mice. Importantly, one study showed that mice treated with osimertinib did not demonstrate weight loss, a sign of toxicity.

Researchers also plan to take a precision medicine approach when designing clinical trials for new inhibitors by using genetic profiling to help determine which patients' tumors overexpress ABC transporters and are thus most likely to benefit from treatment that includes an ABC transporter inhibitor.

Why some melanoma patients do not respond to immunotherapy

Credit: Pixabay/CC0 Public Domain

By harnessing the immune system against cancer, immunotherapies have revolutionized the way some types of cancer are treated. But most patients—across cancer types—do not respond, and in most cases, scientists are at a loss as to why.

Researchers at Columbia and MIT have created a new technique that can uncover nearly all of the tricks cancer cells use to evade immunotherapies, which could lead to the development of more effective treatments.

The researchers tested their new technique with cancer cells and matching immune cells from melanoma patients and identified previously unknown resistance mechanisms to immune checkpoint inhibitors, a powerful and widely used class of immunotherapy drugs.

The findings were published online March 1 in Nature Genetics.

Immunotherapies fail or stop working in two-thirds of melanoma patients

Immune checkpoint inhibitors are drugs that are designed to release the "brakes" that prevent the immune system from operating at full power and attacking the cancer cells.

"With drugs called immune checkpoint inhibitors, we're now getting as close as we have ever been to curing one-third of patients with metastatic melanoma, even at a stage when the disease has spread throughout the body," says study leader Benjamin Izar, MD, Ph.D., assistant professor of medicine at Columbia University Vagelos College of Physicians and Surgeons.

"So the question is, what is happening in the other two-thirds of patients?" Izar says. "What are the mechanisms of intrinsic or adaptive drug resistance?"

In a previous study published in Cell in 2018, Izar and his team identified 250 genes in metastatic melanoma cells that allow them to evade the immunotherapy. The new study was devised to provide a systematic way to functionally decipher how each of those genes contributes to immunotherapy resistance.

First test of CRISPR tool

The study is the first test of a new tool that combines two advanced technologies—CRISPR gene editing and single-cell RNA and -protein sequencing—in a way that allows researchers to determine the full landscape of how cancer cells can evade the immune system.

Using CRISPR, the researchers inactivated those 250 genes—one by one but in a pooled fashion—to create a mixture of 250 batches of melanoma cells, each with a different mutation. The entire heterogenous population of "edited" cancer cells was then exposed to T cells—the immune cells unleashed by checkpoint inhibitors in patients.

Cells that resisted being killed by T cells were isolated, and a snapshot of all active processes within these cells was measured using single-cell RNA and protein profiling, providing a high-resolution molecular map of several gene perturbations resulting in immune escape.

"Our approach is unique in that we study these mechanisms in patient-derived models, and rather than looking at how a gene changes a cell's phenotype one gene at a time, we were able to study many genes with potential roles in drug resistance in patients in one sweep. It's the first time that such tools have been used at such a large scale," says Izar.

All told, close to a quarter million cells were analyzed. Computational biology tools, developed by Izar and co-senior author Aviv Regev, Ph.D., professor of biology at MIT, were employed to make sense of this tremendous data set.

New and old resistance mechanisms identified

The analysis identified new mechanisms of resistance to immunotherapy along with mechanisms that were previously known. "Basically, we recovered the majority of known mechanisms described over the last 10 years—validating that our approach works and giving us confidence that the new findings are important," Izar says.

"We also uncovered many new mechanisms of resistance," says Johannes C. Melms, MD, a postdoctoral fellow in the Izar lab and the study's co-first author (with Chris J. Frangieh, a doctoral student at MIT).

One of the new resistance mechanisms involves a gene called CD58. "Our data suggests that loss of CD58 in melanoma cells confers immune escape through three potential mechanisms: impairing activation of T cells, reducing the ability of T cells getting into the tumor, and increasing the production of PD-L1," Melms says. "Because the CD58 gene is not mutated per se but rather just turned off, it raises the possibility that therapies that turn it on could overcome drug resistance in some patients."

The researchers plan to develop therapies to improve response to immunotherapies based on this finding.

Izar and his team expect to learn more about resistance to immunotherapy from the study data. "CD58 is just one of many genes that warrant a closer look," Izar says.

In future experiments, the researchers plan to inactivate various combinations of cancer cell genes at once. "In this study, we looked at what happens to cells when only one gene is inactivated," he says. "But it's likely that no single gene is sufficient to confer all the types of resistance to immunotherapy that we see in clinical practice."

The study focused on melanoma, but the same approach could be used to study resistance to immunotherapy in many other forms of cancer, the researchers note.