Tag Archives: Melanoma

Microbiology

New Vaccine Helps Decrease the Likelihood of Skin Cancer Recurrence and Death

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A recent clinical trial reveals that the combination of an experimental mRNA vaccine with an immunotherapy led to a 44% decrease in the risk of melanoma recurrence or death compared to the use of immunotherapy alone.

The randomized phase 2b trial, which was headed by researchers at NYU Langone Health and its Perlmutter Cancer Center, included both men and women who underwent surgery for the removal of melanoma from their lymph nodes or other organs and were at a heightened risk of the disease reappearing at distant sites from the original cancer.

Among 107 study subjects who were injected with both the experimental vaccine, called mRNA-4157/V940, and the immunotherapy pembrolizumab, the cancer returned in 24 subjects (22.4%) within two years of follow-up, compared with 20 out of 50 (40%) who received only pembrolizumab.

“Our phase 2b study shows that a neoantigen mRNA vaccine, when used in combination with pembrolizumab, resulted in prolonged time without recurrence or death compared with pembrolizumab alone,” said study senior investigator Jeffrey Weber, MD, Ph.D., the deputy director of the Perlmutter Cancer Center.

The phase 2b trial results are to be presented at the annual meeting of the American Association for Cancer Research on April 16 in Orlando, Florida.

While randomized phase 3 trials test whether a treatment is superior to current standard therapies, phase 2 trials like the current study provide preliminary reassurance that one treatment is likely to be better than another, and lead to larger studies to confirm those results. Phase 3 trials of the combination of the mRNA-4157/V940 vaccine with pembrolizumab versus pembrolizumab alone are already planned at NYU Langone and a number of other medical centers globally, said Weber, the Laura and Isaac Perlmutter Professor of Oncology in the Department of Medicine at NYU Grossman School of Medicine.

Study results so far led the United States Food and Drug Administration in February to grant Breakthrough Therapy Designation to mRNA-4157/V940 in combination with pembrolizumab, a designation designed to speed government reviews of trial results.

The current results highlight the role of immune system T cells capable of attacking viruses as well as cancers. To spare normal cells, this system uses “checkpoint” molecules on T cell surfaces to “turn off” their attack against viruses when they clear the infection. The body may recognize tumors as abnormal, but cancer cells hijack checkpoints to turn off, evade and avoid immune responses. Immunotherapies like pembrolizumab seek to block checkpoints, making cancer cells more “visible” and vulnerable again to immune cells.

Immunotherapies have become the mainstay for treating melanoma, although they do not work for all patients because melanoma cells, known for their ability to evade the immune system, can become resistant to immunotherapy. For this reason, researchers have looked at adding vaccines. While most vaccines used today are designed to prevent infections, they can also be tailored to target proteins involved in cancer.

Like the COVID-19 vaccine, mRNA-4157/V940 is based on messenger RNA, a chemical cousin of DNA that provides instructions to cells for making proteins. mRNA cancer vaccines are designed to teach the body’s immune system to recognize cancer cells as different from normal cells. In designing a vaccine against melanoma, researchers attempted to trigger an immune response to specific abnormal proteins, called “neoantigens,” made by cancer cells.

Because the study volunteers all had their tumors removed, researchers were able to analyze their cells for neoantigens that were specific to each melanoma and create a “personalized” vaccine for each patient. As a result, T cells were produced specific to the neoantigen proteins encoded by the mRNA. Those T cells could then attack any melanoma cells trying to grow or spread.

Scientists involved in the study say that the personalized mRNA-4157/V940 vaccine took about six to eight weeks to develop for each patient and could recognize as many as 34 neoantigens. Severe side effects were similar between the two arms of the study, they said, with fatigue being the most common side effect specific to the vaccine reported by patients.

Watch a video with researcher and patient commentary here.

Meeting: AACR Annual Meeting 2023

The study was presented at the annual meeting of the American Association for Cancer Research on Sunday, April 16, 2023, at 11 a.m. EDT in Orlando, Fla., and was titled “A personalized cancer vaccine, mRNA-4157, combined with pembrolizumab in patients with resected high-risk melanoma: Efficacy and safety results from the randomized, open-label Phase 2b mRNA-4157-P201/Keynote-942 trial.

The study was funded by Moderna Inc. of Cambridge, Mass., and Merck of Rahway, NJ. mRNA-4157/V940 is being jointly developed and commercialized by Moderna and Merck. Merck is the manufacturer of pembrolizumab. About 1.3 million Americans are currently diagnosed with some form of melanoma.

Weber consults for and has received less than $10,000 per annum from Merck, Genentech, Astra Zeneca, GSK, Novartis, Nektar, Celldex, Incyte, Biond, Moderna, ImCheck, Sellas, Evaxion, Pfizer, Regeneron, and EMD Serono; has received $10-25,000 from BMS for membership on Advisory Boards; he holds equity in Biond, Evaxion, OncoC4, and Instil Bio; and is on scientific advisory boards for CytoMx, Incyte, ImCheck, Biond, Sellas, Instil Bio, OncoC4, and Neximmune, for which he is remunerated between $10,000-$50,000 dollars. He is not a member of any speaker’s bureau; NYU received research support from BMS, Merck, GSK, Moderna, Pfizer, Novartis, and Astra Zeneca; Weber is one of the co-authors on two patents filed by Moffitt Cancer Center and one patent filed by Biodesix and receives less than $6,000 yearly in royalties. These relationships are being managed in accordance with the policies and practices of NYU Langone Health.

Besides Weber, other study co-investigators are Adnan Khattak, at Hollywood Private Hospitals in Nedlands, Australia; Matteo Carlino, at Westmead Hospital in Westmead, Australia; Tarek Meniawy, at Saint John of God Subiaco Hospital in Subiaco, Australia; George Ansstas, at Washington University in St. Louis, Mo.; Teresa Medina, at University of Colorado in Aurora; Matthew Taylor, at the Earle A. Chiles Research Institute in Portland, Ore.; Kevin Kim, at California Pacific Medical Center Research Institute in Oakland; Meredith McKean, at the Sarah Cannon Research Institute in Nashville, Tenn.; Georgina Long, at Melanoma Institute Australia in Wollstonecraft, Australia; Ryan Sullivan, at Mass General Brigham in Boston; Mark Faries, at The Angeles Clinic and Research Institute in Los Angeles; Thuy Tran, at Yale-New Haven Hospital in New Haven, Conn.; Charles Cowey, at Baylor Scott & White Charles A. Sammons Cancer Center in Dallas; Andrew Pecora, at the John Thuerer Cancer Center in Hackensack, NJ; Jennifer Segar, at the University of Arizona in Tucson; Victoria Atkinson, at Princess Alexandra Hospital in Woolloongabba, Australia; Geoffrey Gibney, at Lombardi Cancer Center in Washington, DC; Jason Luke, at the University of Pittsburgh in Pennsylvania; Sajeve Thomas, at Orlando Health in Florida; Elizabeth Buckbinder, at Dana-Farber Cancer Institute in Boston; Peijie Hou, Lili Zhu, Michelle Brown, Praveen Aanur, and Robert Meehan, at Moderna Inc. in Cambridge, Mass.; and Tal Zaks, at OrbiMed in New York City.

NYU Langone Health / NYU Grossman School of Medicine

Microbiology

Healthy gut bacteria can travel to other parts of the body and boost antitumor immunity

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Reviewed by Emily Henderson, B.Sc.Mar 9 2023

Researchers at UT Southwestern Medical Center have discovered how healthy bacteria can escape the intestine, travel to lymph nodes and cancerous tumors elsewhere in the body, and boost the effectiveness of certain immunotherapy drugs. The findings, published in Science Immunology, shed light on why antibiotics can weaken the effect of immunotherapies and could lead to new cancer treatments.

Scientists have been stumped as to how bacteria inside your gut can have an impact on a cancer in your lungs, breasts, or skin. Now we understand that mechanism much better and, in the future, hope to use this knowledge to better fight cancer.”

Andrew Y. Koh, M.D., Associate Professor of Pediatrics, Microbiology, and in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern

Previous studies, including one led by Dr. Koh at UT Southwestern, have shown an association between the composition of gut microbiomes – the microorganisms found inside the digestive tract – and the effectiveness of cancer treatments that target the immune system, including pembrolizumab (Keytruda) and ipilimumab (Yervoy). However, researchers have reached conflicting conclusions about the ideal balance of microorganisms to optimize therapy, with studies pointing to different beneficial bacteria.

Dr. Koh and colleagues used mice with melanoma tumors to probe how the drugs, called immune checkpoint inhibitors, affected the movement of gut microbes through the body. They found that immune checkpoint inhibitors, which boost the activity of the immune system against tumors, also cause inflammation in the digestive system that leads to remodeling of lymph nodes in the gut.

Due to these changes, bacteria can leave the intestines and travel to lymph nodes near the tumor and the tumor itself, the researchers found. Here, the microbes activate a set of immune cells that act to kill tumor cells.

“Immune checkpoint inhibitors work by releasing the brakes on the immune system to target cancer,” said Dr. Koh, who is also Director of the Cellular and ImmunoTherapeutics Program at UTSW and Children’s Health. “What we think is that these microorganisms and the immune cells they’re activating are essentially pressing on the accelerator of the immune system at the same time.”

The findings suggest that a course of antibiotics, which can eliminate most gut microbes, is detrimental to immune checkpoint inhibitors because the bacteria can no longer play this role of immune accelerant. It also helps explain why researchers have found many types of bacteria in patient microbiomes that seem to be beneficial for treatment.

“As long as a subset of beneficial bacteria can translocate from the gut to the lymph node or tumor, it may not matter exactly which bacteria it is,” said Dr. Koh.

Dr. Koh’s team is now working toward the development of bacterial-based treatments to boost the efficacy of immune checkpoint inhibitors.

Other UTSW researchers who contributed to the study include first author and UTSW graduate student Yongbin Choi, Lora Hooper, Jake Lichterman, Laura Coughlin, Nicole Poulides, Wenling Li, Priscilla Del Valle, Suzette Palmer, Shuheng Gan, Jiwoong Kim, Xiaowei Zhan, Yajing Gao, and Bret Evers.

Dr. Hooper, a Howard Hughes Medical Institute Investigator, holds the Jonathan W. Uhr, M.D. Distinguished Chair in Immunology and is a Nancy Cain and Jeffrey A. Marcus Scholar in Medical Research, in honor of Dr. Bill S. Vowell.

The research was supported by funding from the National Institutes of Health (R01 CA231303, K24 AI123163, R01 DK070855), the Crow Family Fund, the UT Southwestern Medical Center and Children’s Health Cellular and ImmunoTherapeutics Program, National Research Service Award-Integrative Immunology Training Grant (5T32AI005284-43), The Welch Foundation (I-1874), and the Howard Hughes Medical Institute.

Source:

UT Southwestern Medical Center

Journal reference:

Choi, Y., et al. (2023) Immune checkpoint blockade induces gut microbiota translocation that augments extraintestinal antitumor immunity. Science Immunology. doi.org/10.1126/sciimmunol.abo2003.

Microbiology

Moderna’s experimental cancer vaccine treats but doesn’t prevent melanoma – a biochemist explains how it works

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Media outlets have reported the encouraging findings of clinical trials for a new experimental vaccine developed by the biotech company Moderna to treat an aggressive type of skin cancer called melanoma.

Although this is potentially very good news, it occurred to me that the headlines may be unintentionally misleading. The vaccines most people are familiar with prevent disease, whereas this experimental new skin cancer vaccine treats only patients who are already sick. Why is it called a vaccine if it does not prevent cancer?

I am a biochemist and molecular biologist studying the roles that microbes play in health and disease. I also teach cancer genetics to medical students and am interested in how the public understands science. While preventive and therapeutic vaccines are administered for different health care goals, they both train the immune system to recognize and fight off a specific disease agent that causes illness.

Most vaccines are administered to healthy people before they get sick to prevent illnesses caused by viruses or bacteria. These include vaccines that prevent polio, measles, COVID-19 and many other diseases. Researchers have also developed vaccines to prevent some types of cancers that are caused by such viruses as the human papillomaviruses and Epstein-Barr virus.

Your immune system recognizes objects such as certain microbes and allergens that do not belong in your body and initiates a series of cellular events to attack and destroy them. Thus, a virus or bacterium that enters the body is recognized as something foreign and triggers an immune response to fight off the microbial invader. This results in a cellular memory that will elicit an even faster immune response the next time the same microbe intrudes.

The problem is that sometimes the initial infection causes serious illness before the immune system can mount a response against it. While you may be better protected against a second infection, you have suffered the potentially damaging consequences of the first one.

This is where preventive vaccines come in. By introducing a harmless version or a portion of the microbe to the immune system, the body can learn to mount an effective response against it without causing the disease.

For example, the Gardasil-9 vaccine protects against the human papillomavirus, or HPV, which causes cervical cancer. It contains protein components found in the virus that cannot cause disease but do elicit an immune response that protects against future HPV infection, thereby preventing cervical cancer.

Unlike cervical cancer, skin melanoma isn’t caused by a viral infection, according the latest evidence. Nor does Moderna’s experimental vaccine prevent cancer as Gardasil-9 does.

The Moderna vaccine trains the immune system to fight off an invader in the same way preventive vaccines most people are familiar with do. However, in this case the invader is a tumor, a rogue version of normal cells that harbors abnormal proteins that the immune system can recognize as foreign and attack.

What are these abnormal proteins and where do they come from?

All cells are made up of proteins and other biological molecules such as carbohydrates, lipids and nucleic acids. Cancer is caused by mutations in regions of genetic material, or DNA, that encode instructions on what proteins to make. Mutated genes result in abnormal proteins called neoantigens that the body recognizes as foreign. That can trigger an immune response to fight off a nascent tumor. However, sometimes the immune response fails to subdue the cancer cells, either because the immune system is unable to mount a strong enough response or the cancer cells have found a way to circumvent the immune system’s defenses.

Moderna’s experimental melanoma vaccine contains genetic information that encodes for portions of the neoantigens in the tumor. This genetic information is in the form of mRNA, which is the same form used in the Moderna and Pfizer-BioNtech COVID-19 vaccines. Importantly, the vaccine cannot cause cancer, because it encodes for only small, nonfunctional parts of the protein. When the genetic information is translated into those protein pieces in the body, they trigger the immune system to mount an attack against the tumor. Ideally, this immune response will cause the tumor to shrink and disappear.

Notably, the Moderna melanoma vaccine is tailor-made for each patient. Each tumor is unique, and so the vaccine needs to be unique as well. To customize vaccines, researchers first biopsy the patient’s tumor to determine what neoantigens are present. The vaccine manufacturer then designs specific mRNA molecules that encode those neoantigens. When this custom mRNA vaccine is administered, the body translates the genetic material into proteins specific to the patient’s tumor, resulting in an immune response against the tumor.

Vaccines are a form of immunotherapy, because they treat diseases by harnessing the immune system. However, other immunotherapy cancer drugs are not vaccines because, while they also stimulate the immune system, they do not target specific neoantigens.

In fact, the Moderna vaccine is co-administered with the immunotherapy drug pembrolizumab, which is marketed as Keytruda. Why are two drugs needed?

Certain immune cells called T-cells have molecular accelerator and brake components that serve as checkpoints to ensure they are revved up only in the presence of a foreign invader such as a tumor. However, sometimes tumor cells find a way to keep the T-cell brakes on and suppress the immune response. In these cases, the Moderna vaccine correctly identifies the tumor, but T-cells cannot respond to it.

Pembrolizumab, however, can bind directly to a brake component on the T-cell, inactivating the brake system and allowing the immune cells to attack the tumor.

So why can’t the Moderna vaccine be administered to healthy people to prevent melanoma before it arises?

Cancers are highly variable from person to person. Each melanoma harbors a different neoantigen profile that cannot be predicted in advance. Therefore, a vaccine cannot be developed in advance of the illness.

The experimental mRNA melanoma vaccine, currently still in early-phase clinical trials, is an example of the new frontier of personalized medicine. By understanding the molecular basis of diseases, researchers can explore how their underlying causes vary among people, and offer personalized therapeutic options against those diseases.


Mark R. O’Brian

The Conversation

Microbiology

Novel immunotherapy offers a promising new strategy to fight hard-to-treat cancers

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Reviewed by Emily Henderson, B.Sc.Dec 16 2022

Scientists at UC San Francisco (UCSF) have engineered T cells to produce a potent anti-cancer cytokine, but only when they encounter tumor cells. The immunotherapy eliminated melanoma and pancreatic cancer in mice without major side effects, and it offers a promising new strategy for fighting these and other hard-to-treat cancers.

The cells deliver IL-2, a powerful inflammatory molecule that is naturally produced by the immune system. IL-2 supercharges T cells, immune cells that can kill cancer cells and also protect against infection. While oncologists have known for decades that IL-2 has potent anti-cancer activity, its use has been limited by the toxic response it produces when given systemically.

In the study, published Dec. 15, 2022, in Science, the researchers were able to keep the cytokine contained within the cancer by programming the tumor-infiltrating T cells to make their own IL-2 when they recognized a cancer cell.

We’ve taken advantage of the ability of these cells to be local delivery agents and to crank out their T-cell amplifiers only when they recognize they’re in the right place. I think this is a model for how we can use cell therapies to deliver many types of potent but toxic therapeutic agents in a much more targeted manner.”

Wendell Lim, PhD, the Byers Distinguished Professor in cellular and molecular biology, director of the UCSF Cell Design Institute and senior author on the study

Slipping past the barriers

Cellular therapies have been highly effective against many blood cancers, where the cells are easily accessible because they are floating freely. Solid tumors, however, build multiple defensive walls that prevent therapeutic T cells from entering. And even if the cells do get into the tumor, they often tire out before they’re able to finish off the cancerous cells.

Since the 1980’s, oncologists have known that high doses of IL-2 enable T cells to overcome these barriers, and the cytokine has been used as cancer therapy in challenging cancer cases. But simply infusing patients systemically with IL-2 can cause high fever, leaky blood vessels, and organ failure.

Lim and lead author Greg Allen, MD, PhD, adjunct assistant professor of medicine and a fellow at the Cell Design Institute, aimed to tame IL-2’s effects by engineering cells that enhance the cancer-killing immune response only where it’s needed: in the tumor.

They chose to go after notoriously difficult-to-treat tumors, like those of the pancreas, ovary and lung, that form nearly iron-clad barriers against T cells.

To engineer cells T cells that could sense when they were in the tumor, the researchers used a synthetic Notch (or synNotch) receptor, a flexible type of molecular sensor, which Lim’s lab developed several years earlier. These receptors span the cell membrane, with ends that protrude both inside and outside the cell. The outside portion recognizes and binds to tumor cells, triggering the inside portion to set the production of IL-2 in motion.

The team tested the synNotch cells on a number of deadly tumors, including melanoma and pancreatic cancer, and found that the cells worked exactly as planned.

“We were able to design these therapeutic cells to slip past the tumor’s defensive barriers. Once in the tumor, they could establish a foothold, and begin effectively killing cancerous cells,” said Allen. “We got on top of these tumors and in some cases cured them.”

A positive-feedback circuit

The approach owes its success to engineering a circuit in the cell that amplifies the immune response in a controlled way. This induces the cell to produce IL-2 only under the specific conditions it’s programmed to recognize.

“This induction circuit is really a positive-feedback loop, an important element behind making these designer T cells that are able to operate so effectively,” Allen said.

The circuit begins when the synNotch receptor tells the T cell to make IL-2. That IL-2 feeds back on the cell, causing it to divide, in turn creating more cells that make even more IL-2. The entire process is confined within the tumor, protecting the rest of the body from harm.

Allen, who is both a researcher and an oncologist, hopes to begin testing the therapeutic approach in clinical trials with pancreatic cancer patients in 2024.

“The most advanced immunotherapies are just not working in a lot of these difficult solid tumors,” he said. “We think this type of design can overcome one of the major barriers and do it in a way that’s safe and free of side effects.”

Source:

University of California – San Francisco

Journal reference:

Allen, G.M., et al. (2022) Synthetic cytokine circuits that drive T cells into immune-excluded tumors. Science. doi.org/10.1126/science.aba1624.

Microbiology

Research findings could bolster the effectiveness of immune-checkpoint therapy

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Reviewed by Emily Henderson, B.Sc.Nov 16 2022

Immune checkpoint inhibitors such as Keytruda and Opdivo work by unleashing the immune system’s T cells to attack tumor cells. Their introduction a decade ago marked a major advance in cancer therapy, but only 10% to 30% of treated patients experience long-term improvement. In a paper published online today in The Journal of Clinical Investigation (JCI), scientists at Albert Einstein College of Medicine describe findings that could bolster the effectiveness of immune-checkpoint therapy.

Rather than rally T cells against cancer, the Einstein research team used different human immune cells known as natural killer (NK) cells-;with dramatic results.

We believe the novel immunotherapy we’ve developed has great potential to move into clinical trials involving various types of cancer.”

Xingxing Zang, M.Med., Ph.D., Study Leader

Xingxing Zang is the the Louis Goldstein Swan Chair in Cancer Research and professor of microbiology & immunology, of oncology, of urology, and of medicine at Einstein and a member of the Cancer Therapeutics Program of the Montefiore Einstein Cancer Center.

Telling friend from foe

The surfaces of immune cells are studded with receptors known as “checkpoint” proteins, which prevent immune cells from straying beyond their usual targets (pathogen-infected cells and cancer cells). When checkpoint receptors on immune cells bind with proteins expressed by the body’s own normal cells, the interaction puts the brakes on a possible immune-cell attack. Diabolically, most types of cancer cells express proteins that bind with checkpoint proteins, tricking immune cells into standing down and not attacking the tumor.

Immune checkpoint inhibitors are monoclonal antibodies designed to short-circuit immune-cell/cancer-cell interactions by blocking either the tumor proteins or the immune-cell receptors that bind with tumor proteins. With no brakes to impede them, immune cells can attack and destroy cancer cells.

New focus on natural killer cells

The limited effectiveness of checkpoint inhibitors prompted Dr. Zang and other scientists to look at checkpoint pathways involving NK cells, which-;like T cells-;play major roles in eliminating unwanted cells. A cancer-cell protein called PVR soon captured their attention. “We realized that PVR may be a very important protein that human cancers use to hobble the immune system’s attack,” said Dr. Zang.

PVR protein is usually absent or very scarce in normal tissues but is found in abundance in many types of tumors including colorectal, ovarian, lung, esophageal, head and neck, stomach, and pancreatic cancer as well as myeloid leukemia and melanoma. Moreover, PVRs appeared to inhibit T cell and NK cell activity by binding to a checkpoint protein called TIGIT-;prompting efforts to interrupt the TIGIT/PVR pathway by using monoclonal antibodies made against TIGIT. More than 100 clinical trials targeting TIGIT are now in progress worldwide. However, several clinical studies including two large phase 3 clinical trials have recently failed to improve cancer outcomes.

Recognizing the role of a new receptor

Meanwhile, the cancer-cell protein PVR was found to have another “binding partner” on NK cells: KIR2DL5. “We hypothesized that PVR suppresses NK cell activity not by binding with TIGIT but by binding with the recently recognized KIR2DL5,” said Dr. Zang. To find out, he and his colleagues synthesized a monoclonal antibody targeting KIR2DL5 and carried out in vitro and in vivo experiments using the antibody.

In their JCI paper, Dr. Zang and colleagues demonstrated that KIR2DL5 is a commonly occurring checkpoint receptor on the surface of human NK cells, which PVR cancer proteins use to suppress immune attack. In studies involving humanized animal models of several types of human cancers, the researchers showed that their monoclonal antibody against KIR2DL5-;by blocking the KIR2DL5/PVR pathway-;allowed NK cells to vigorously attack and shrink human tumors and prolong animal survival (see accompanying illustration). “These preclinical findings raise our hopes that targeting the KIR2DL5/PVR pathway was a good idea and that the monoclonal antibody we’ve developed may be an effective immunotherapy,” said Dr. Zang.

Einstein has filed a patent application for KIR2DL5/PVR immune checkpoint including antibody drugs and is interested in a partnership to further develop and commercialize the technology.

Dr. Zang has previously developed and patented more than 10 immune checkpoint inhibitors. One of those inhibitors is now being tested in China in phase 2 clinical trials involving several hundred patients with advanced solid cancers (non-small cell lung cancer, small cell lung cancer, nasopharyngeal cancer, head and neck cancer, melanoma, lymphoma) or recurrent/refractory blood cancers (acute myeloid leukemia, myelodysplastic syndromes). Another of Dr. Zang’s immune checkpoint inhibitors will be evaluated starting next year in cancer clinical trials in the United States.

Source:

Albert Einstein College of Medicine

Journal reference:

Ren, X., et al. (2022) Blockade of the immunosuppressive KIR2DL5/PVR pathway elicits potent human NK cell-mediated antitumor immunity. Journal of Clinical Investigation. doi.org/10.1172/JCI163620.

Microbiology

Chinese scientists reveal a previously undefined pathway by which Mtb counteracts host immunity

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Reviewed by Emily Henderson, B.Sc.Oct 13 2022

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains a leading infectious threat to public health worldwide. It is estimated to have infected 2–3 billion people and causes ~1.5 million deaths each year.

Now, a group of Chinese scientists has described a previously undefined pathway by which Mtb counteracts host immunity. Specifically, the researchers identified the known Mtb protein tyrosine phosphatase PtpB as a phospholipid phosphatase that inhibits the host inflammasome-pyroptosis pathway by hijacking host ubiquitin.

The study, carried out by Prof. LIU Cuihua’s group at the Institute of Microbiology of the Chinese Academy of Sciences (IMCAS), in collaboration with Prof. QIU Xiaobo from Beijing Normal University, was published in Science.

Dr. LIU’s group has been investigating the molecular mechanisms underlying Mtb-host interactions, and previous studies from her group have provided potential targets for the development of anti-TB treatments based on pathogen-host interaction interfaces.

Mtb is an intracellular pathogen that has developed numerous intracellular survival strategies, and the intricate and dynamic interactions between Mtb and its host determine the occurrence, progression, and outcomes of TB. One interesting feature evolved by Mtb is a set of eukaryotic-like effectors, but their host targets and regulatory roles in pathogen-host interactions have been largely unexplored.

In this study, LIU’s group examined the whole genome of Mtb to predict secreted eukaryotic-like proteins possessing eukaryotic-like motifs or domains that might target host factors directly. These Mtb effector proteins were then subjected to further experimental analyses using an inflammasome reconstitution system for screening inhibitors of inflammasome-pyroptosis pathways.

Out of 201 predicted Mtb-secreted eukaryotic proteins, the scientists identified PtpB as a key bacterial effector that was abundantly secreted by Mtb to inhibit both NOD-like receptor protein 3 (NLRP3) and absent in melanoma 2 (AIM2) inflammasome pathways.

Subsequent experiments demonstrated that PtpB inhibited GSDMD-dependent cytokine release and pyroptosis to promote Mtb intracellular survival in macrophages. Mechanistically, Mtb-secreted PtpB targets and dephosphorylates host plasma membrane phosphatidylinositol-4-monophosphate (PI4P) and phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2] to inhibit membrane localization of the N-terminal cleavage fragment of GSDMD (GSDMD-N), thus preventing GSDMD-mediated immune responses.

Interestingly, this phosphatase activity requires PtpB binding to ubiquitin via its unique ubiquitin-interacting motif (UIM)-like region. Disruption of phospholipid phosphatase activity or the UIM-like region of PtpB enhanced host GSDMD-dependent immune responses, thus reducing intracellular pathogen survival.

This study reveals a previously unrecognized strategy by which pathogens inhibit pyroptosis and counteract host immunity by altering host membrane composition. Its results might lead to the development of a potential TB treatment by targeting the PtpB-Ub-phospholipid-pyroptosis axis.

Source:

Chinese Academy of Sciences Headquarters

Journal reference:

Chai, Q., et al. (2022) A bacterial phospholipid phosphatase inhibits host pyroptosis by hijacking ubiquitin. Science. doi.org/10.1126/science.abq0132.