Road signs for immune defense cells

Organisms are constantly invaded by pathogens such as viruses. Our immune system swings into action to combat these pathogens immediately. The innate non-specific immune response is triggered first, and the adaptive or acquired immune response follows. In this second defence reaction, specialised cytotoxic T lymphocytes known as killer T cells destroy cells in the body that have been infected and thus prevent damage from spreading. Humans possess a repertoire of some 20 million T cell clones with varying specificity to counter the multitude of infectious agents that exist. But how do the killer T cells know where danger is coming from? How do they recognise that something is wrong inside a cell in which viruses are lurking? They can't just have a quick peek inside.

At this point, antigen processing comes into play. The process can be compared to making a road sign. The molecular barcode is "processed" or assembled in the cell -- in the endoplasmic reticulum, to be exact. Special molecules are used in its making, the MHC class I molecules. They are loaded with information about the virus invader in a molecular machine, the peptide loading complex (PLC). This information consists of peptides, fragments of the protein foreign to the body. These fragments also contain epitopes, the molecular segments that elicit a specific immune response. During the loading process, an MHC I-peptide epitope complex thus forms, and this is the road sign that is then transported to the surface of the cell and presented in a readily accessible form to the killer T cells -- we could almost say that it is handed to them on a silver platter. The chaperones, special accessory proteins that assist the correct folding of proteins with complex structures in cells, also play a significant role.

The chaperones that support antigen processing are calreticulin, ERp57, and tapasin. But how do they work together? And how important are they for antigen processing? An answer has now been supplied by a study carried out by Goethe University Frankfurt and the University of Oxford and published in Nature Communications. "With this study, we have achieved a breakthrough in our understanding of cellular quality control," says Professor Robert Tampé, Director of the Institute of Biochemistry at Goethe University Frankfurt. He explains the logic underlying this quality control process as follows: "The MHC I-peptide epitope complex, the road sign, needs to be exceptionally stable, and for quite a long time, because the adaptive immune response does not start instantly. It needs 3 to 5 days to get going." So, the sign must not collapse after one day; that would be disastrous, as the immune defence cells would then fail to detect cells infected by a virus. This would mean that they would not destroy these cells and the virus would be able to continue its spread unhindered. A similar problem would arise if a cell in the body had mutated into a tumour cell: the threat would remain undetected. It is imperative, therefore, that a quality control system is in place.

As the study shows, the chaperones are central process components: they give the road sign the long-term stability it must have by making a strict selection. By rejecting the short-lived virus fragments in the mass of available material, they ensure that only MHC I molecules loaded with the best and most stable peptide epitopes in complex with MHC I are released from the peptide loading complex. The chaperones have different tasks in this selection process that is so important for the adaptive immune response, Tampé says: "Tapasin acts as a catalyst that accelerates the exchange of suboptimal peptide epitopes for optimal epitopes. Calreticulin and ERp57, in contrast, are deployed universally." This concerted approach ensures that only stable MHC I complexes with optimal peptide epitopes reach the cell surface and perform their role of guiding the killer T cells to the infected or mutated cell.

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Novel antibody drug wakes up the body's defense system in advanced-stage cancer

Researchers at the University of Turku, Finland, showed that the antibody treatment reactivates the immune defense in patients with advanced-stage cancer. The treatment alters the function of the body's phagocytes and facilitates extensive activation of the immune system.

The immune defense is the body's own defense system equipped to combat cancer. However, cancer learns to hide from immune attacks and harnesses this system to promote its own growth. Therefore, it would be beneficial to be able to return the immune defense back to restricting the advancement of cancer.

Macrophages, a type of white blood cell, are central in the fight against cancer. Cancer educates macrophages to subdue the defense system and renders many treatments targeting the immune system ineffective.

Academy Research Fellow Maija Hollmén's research group has searched for means of altering the activity of macrophages in order to direct the immune defense to attack cancer. The antibody bexmarilimab, developed based on this research and in collaboration with Faron Pharmaceuticals, is currently undergoing clinical trials in patients. Hollmén's group has studied the changes occurring in the defense systems of patients with cancer following antibody treatment.

"In the majority of patients, the antibody treatment activated killer T cells, which are the body's strike force against cancer. Additionally, the antibody treatment successfully lowered the suppressive potential of macrophage precursors travelling in the blood circulation. The patients also showed increases in certain mediators of inflammation and types of white blood cell in the blood," describes Hollmén.

"The activation of the killer T cells is a very promising demonstration of the antibody's capability to boost the defense system against cancer. The treated patients had very advanced and poorly treatable cancers, which highlights the significance of the results," says Doctoral Candidate Jenna Rannikko.

Bexmarilimab May Benefit Patients for Whom Current Treatment Options Are Ineffective

The research also yielded new information on the mode of action of bexmarilimab. The antibody binds the molecule Clever-1 present on macrophages and alters its function.

Clever-1 transports material needless to the body inside macrophages to be degraded. Objects disposed in this manner are swept under the rug, in a manner of speaking. This kind of concealment is beneficial for the body's natural balance and helps to avoid stirring the immune defense unnecessarily.

"However, cells originating from cancer should be detected. When the antibody is used to block Clever-1 from performing its cleaning job, it facilitates the activation of cells of the immune defense. This in part leads to the waking up of the T cells in patients," describes Doctoral Candidate Miro Viitala.

There is demand for treatments that boost the activity of the immune defense since the current options on the market only help some patients.

"Bexmarilimab's mode of action is different from the drug treatments against cancer currently on the market. Therefore, it can be beneficial for patients for whom current treatment options are ineffective," concludes Postdoctoral Researcher Reetta Virtakoivu.

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Immune system mounts a lasting defense after recovery from COVID-19, researchers find

 

Coronavirus illustration.

As the number of people who have fought off SARS-CoV-2 climbs ever higher, a critical question has grown in importance: How long will their immunity to the novel coronavirus last? A new Rockefeller study offers an encouraging answer, suggesting that those who recover from COVID-19 are protected against the virus for at least six months, and likely much longer.

The findings, published in Nature, provide the strongest evidence yet that the immune system "remembers" the virus and, remarkably, continues to improve the quality of antibodies even after the infection has waned. Antibodies produced months after the infection showed increased ability to block SARS-CoV-2, as well as its mutated versions such as the South African variant.

The researchers found that these improved antibodies are produced by immune cells that have kept evolving, apparently due to a continued exposure to the remnants of the virus hidden in the gut tissue.

Based on these findings, researchers suspect that when the recovered patient next encounters the virus, the response would be both faster and more effective, preventing re-infection.

"This is really exciting news. The type of immune response we see here could potentially provide protection for quite some time, by enabling the body to mount a rapid and effective response to the virus upon re-exposure," says Michel C. Nussenzweig, the Zanvil A. Cohn and Ralph M. Steinman Professor and head of the Laboratory of Molecular Immunology, whose team has been tracking and characterizing antibody response in Covid-19 patients since the early days of the pandemic in New York.

Long-lasting memory

Antibodies, which the body creates in response to infection, linger in the blood plasma for several weeks or months, but their levels significantly drop with time. The immune system has a more efficient way of dealing with pathogens: instead of producing antibodies all the time, it creates memory B cells that recognize the pathogen, and can quickly unleash a new round of antibodies when they encounter it a second time.

But how well this memory works depends on the pathogen. To understand the case with SARS-CoV-2, Nussenzweig and his colleagues studied the antibody responses of 87 individuals at two timepoints: one month after infection, and then again six months later. As expected, they found that although antibodies were still detectable by the six-month point, their numbers had markedly decreased. Lab experiments showed that the ability of the participants' plasma samples to neutralize the virus was reduced by five-fold.

In contrast, the patients' memory B cells, specifically those that produce antibodies against SARS-CoV-2, did not decline in number, and even slightly increased in some cases. "The overall numbers of memory B cells that produced antibodies attacking the Achilles' heel of the virus, known as the receptor-binding domain, stayed the same," says Christian Gaebler, a physician and immunologist in Nussenzweig's lab. "That's good news because those are the ones that you need if you encounter the virus again."

Viral stowaways

A closer look at the memory B cells revealed something surprising: these cells had gone through numerous rounds of mutation even after the infection resolved, and as a result the antibodies they produced were much more effective than the originals. Subsequent lab experiments showed this new set of antibodies were better able to latch on tightly to the virus and could recognize even mutated versions of it.

"We were surprised to see the memory B cells had kept evolving during this time," Nussenzweig says. "That often happens in chronic infections, like HIV or herpes, where the virus lingers in the body. But we weren't expecting to see it with SARS-CoV-2, which is thought to leave the body after infection has resolved."

SARS-CoV-2 replicates in certain cells in the lungs, upper throat, and small intestine, and residual viral particles hiding within these tissues could be driving the evolution of memory cells. To look into this hypothesis, the researchers have teamed up with Saurabh Mehandru, a former Rockefeller scientist and currently a physician at Mount Sinai Hospital, who has been examining biopsies of intestinal tissue from people who had recovered from COVID-19 on average three months earlier.

In seven of the 14 individuals studied, tests showed the presence of SARS-CoV-2's genetic material and its proteins in the cells that line the intestines. The researchers don't know whether these viral left-overs are still infectious or are simply the remains of dead viruses.

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Discovery about how cancer cells evade immune defenses inspires new treatment approach

 Cancer cells are known for spreading genetic chaos. As cancer cells divide, DNA segments and even whole chromosomes can be duplicated, mutated, or lost altogether. This is called chromosomal instability, and scientists at Memorial Sloan Kettering have learned that it is associated with cancer's aggressiveness. The more unstable chromosomes are, the more likely that bits of DNA from these chromosomes will end up where they don't belong: outside of a cell's central nucleus and floating in the cytoplasm.

Cells interpret these rogue bits of DNA as evidence of viral invaders, which sets off their internal alarm bells and leads to inflammation. Immune cells travel to the site of the tumor and churn out defensive chemicals. A mystery has been why this immune reaction, triggered by the cancer cells, does not spell their downfall.

"The elephant in the room is that we didn't really understand how cancer cells were able to survive and thrive in this inflammatory environment," says Samuel Bakhoum, a physician-scientist at MSK and a member of the Human Oncology and Pathogenesis Program.

According to a new study from Dr. Bakhoum's lab published December 28 in the journal Cancer Discovery, the reason has to do, in part, with a molecule sitting on the outside of the cancer cells that destroys the warning signals before they ever reach neighboring immune cells.

The findings help to explain why some tumors do not respond to immunotherapy, and -- equally important -- suggest ways to sensitize them to immunotherapy.

Detecting Dangerous DNA

The warning system Dr. Bakhoum studies is called cGAS-STING. When DNA from a virus (or an unstable cancer chromosome) lands in a cell's cytoplasm, cGAS binds to it, forming a compound molecule called cGAMP, which serves as a warning signal. Inside the cell, this warning signal activates an immune response called STING, which addresses the immediate problem of a potential viral invader.

In addition, much of the cGAMP also travels outside the cell where it serves as a warning signal to neighboring immune cells. It activates their STING pathway and unleashes an immune attack against the virally infected cell.

Previous work from the Bakhoum lab had shown that cGAS-STING signaling inside of cancer cells causes them to adopt features of immune cells -- in particular, the capacity to crawl and migrate -- which aids their ability to metastasize. This provided part of the answer to the question of how cancer cells survive inflammation and aid metastasis in the process. The new research shows how the cancer cells cope with the warning signals that activated cGAS-STING releases into the environment. A scissor-like protein shreds the signals, providing a second way the cells can thwart the threat of immune destruction.

Examples of human triple negative breast cancer staining negative (left) and positive (right) for ENPP1 expression. Examples of human triple negative breast cancer staining negative (left) and positive (right) for ENPP1.

The scissor-like protein that coats cancer cells is called ENPP1. When cGAMP finds its way outside the cell, ENPP1 chops it up and prevents the signal from reaching immune cells. At the same time, this chopping releases an immune-suppressing molecule called adenosine, which also quells inflammation.

Through a battery of experiments conducted in mouse models of breast, lung, and colorectal cancers, Dr. Bakhoum and his colleagues showed that ENPP1 acts like a control switch for immune suppression and metastasis. Turning it on suppresses immune responses and increases metastasis; turning it off enables immune responses and reduces metastasis.

The scientists also looked at ENPP1 in samples of human cancers. ENPP1 expression correlated with both increased metastasis and resistance to immunotherapy.

Empowering Immunotherapy

From a treatment perspective, perhaps the most notable finding of the study is that flipping the ENPP1 switch off could increase the sensitivity of several different cancer types to immunotherapy drugs called checkpoint inhibitors. The researchers showed that this approach was effective in mouse models of cancer.

Several companies -- including one that Dr. Bakhoum and colleagues founded -- are now developing drugs to inhibit ENPP1 on cancer cells.

Dr. Bakhoum says it's fortunate that ENPP1 is located on the surface of cancer cells since this makes it an easier target for drugs designed to block it.

It's also relatively specific. Since most other tissues in a healthy individual are not inflamed, drugs targeting ENPP1 primarily affect cancer.

Finally, targeting ENPP1 undercuts cancer in two separate ways: "You're simultaneously increasing cGAMP levels outside the cancer cells, which activates STING in neighboring immune cells, while you're also preventing the production of the immune-suppressive adenosine. So, you're hitting two birds with one stone," Dr. Bakhoum explains.

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