The international study was published in the peer-reviewed Journal of Hepatology.

“Our study found that we can treat advanced-stage liver cancer patients with immunotherapy and shrink their tumors, effectively turning them into early-stage patients and making them candidates for liver transplantation,” said Ju Dong Yang, MD, medical director of the Liver Cancer Program at Cedars-Sinai Cancer and senior author of the study.

Liver cancer causes no symptoms in the early stages, so many patients aren’t diagnosed until a later stage, said Yang, who is also an associate professor of Medicine at Cedars-Sinai.

“Immunotherapy has transformed care for many cancer types, including advanced-stage liver cancer,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Foundation Distinguished Chair. “But for these patients, liver transplant still seemed out of reach because bolstering the body’s immune system increases the risk of organ rejection.”

Yang said that clinicians believed that a gap between the end of immunotherapy treatment and liver transplant might allow the immune system to return to normal and reduce this risk, but that no large-scale studies had looked at this question.

Yang and fellow investigators reviewed published data on 91 liver cancer patients from Europe, Asia and North America who had received immunotherapy before having a liver transplant, noting rates of transplant rejection, cancer recurrence and overall survival.

“We collected every case that has been published and obtained additional clinical information on each patient,” Yang said. “Based on this, we concluded that with a 90-day gap between the last dose of immunotherapy and liver transplant, the risk of organ rejection is no greater than if the patient had never received immunotherapy.”

Additional studies to confirm these findings are already in the works, and Yang said that based on this evidence, clinicians should feel more comfortable considering organ transplant for advanced liver cancer patients after “downstaging” their cancer with immunotherapy treatment—as long as they observe a 90-day waiting period first.

“This allows time for the immune system to return to normal, and also to monitor the patient to make sure their cancer doesn’t begin to progress after immunotherapy treatment,” Yang said.

Yee Hui Yeo, MD, a Cedars-Sinai gastroenterology fellow, is also a study author.

Additional authors: Mohammad Saeid Rezaee-Zavareh, Tielong Wang, Zhiyong Guo, Parissa Tabrizian, Stephen C. Ward, Fatma Barakat, Tarek I. Hassanein, Dave Shravan, Ajmera Veeral, Sherrie Bhoori, Vincenzo Mazzaferro, David M.H. Chascsa, Margaret C. Liu, Elizabeth S. Aby, John R. Lake, Miguel Sogbe, Bruno Sangro, Maen Abdelrahim, Abdullah Esmail, Andreas Schmiderer, Yasmina Chouik, Mark Rudolph, Davendra Sohal, Heloise Giudicelli, Manon Allaire, Mehmet Akce, Jessica Guadagno, Clara Y. Tow, Hatef Massoumi, Paolo De Simone, Elise Kang, Robyn D. Gartrell, Mercedes Martinez, Ricardo Paz-Fumagalli, Beau B. Toskich, Nguyen H. Tran, Gabriela Azevedo Solino, Dra Mariana Poltronieri Pacheco, Richard S. Kalman, Vatche G. Agopian, Neil Mehta, Neehar D. Parikh, Amit G. Singal.

Funding: Dr. Yang`s research is supported by NCI K08 CA259534. Dr. Singal’s research is supported by NCI R01.  

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The body’s immune system includes white blood cells called phagocytes that function like the video game character Pac-Man, circulating through the body to detect and ingest intruders like bacteria and fungi.

Once the invading microbe is engulfed, a process called phagocytosis, the phagocyte kills it. The microbe is killed by fusing with an intracellular organelle called a phagosome, which contains proteins, that destroy the invader.

David Underhill, PhD, chair of the Department of Biomedical Sciences and the Janis and William Wetsman Family Chair in Inflammatory Bowel Disease, notes that once the microbe is inside, a phagosome generates signals that guide local inflammatory responses, and many of these signals are microbe specific.

“With this knowledge, we developed a novel technique, termed PhagoPL, to identify all of the proteins involved in attacking different kinds of microbes,” said Underhill, senior and corresponding author of the study. “We then used this technique to study three types of phagosomes: one containing yeast, and two containing different types of bacteria.”

Underhill said his team of investigators also found that many proteins found in phagosomes are common to the different types of phagosomes.

“While we found that many phagosome proteins are common with different pathogens, we found that each microbe also recruits unique proteins that are specific to that microbe, suggesting that these proteins help drive inflammatory responses that are targeted for specific microbes,” Underhill said.

Even more unexpected, the Cedars-Sinai investigators found that a cell surface protein called PD-L1 is recruited specifically to yeast-containing phagosomes and turns out to be a fungal-binding receptor. PD-L1 has been previously known to regulate activation of T cells, which help the immune system fight off infections, and researchers say PD-L1 is an exciting protein being targeted by cancer immunotherapy strategies.

“We would never have guessed that PD-L1 would have such a specific role in sensing fungi,” said Kai Li, PhD, a project scientist and lead author of the study. “In fact, we focused our study on PD-L1 because it stood out to us as a protein that we felt really shouldn’t be found associated with these microbes.”

Underhill said the discovery of a novel function for PD-L1 is proof-in-principle of the power of PhagoPL, the new methodology created with broad applicability for the discovery of phagosome proteins and mechanisms of immunity.

Jeffrey A. Golden, MD, executive vice dean of Research and Education and director of the Burns and Allen Research Institute at Cedars-Sinai, said this study is likely to impact future research.

“These findings have provided new insight into how phagocytes function and has the potential to fundamentally change our current view of PD-L1. This information can potentially be leveraged to develop novel, or improve current, anti-tumor immunotherapies,” said Golden, who was not involved in the study.

Because of the versatility of the PhagoPL technique, Underhill and team are eager to apply their findings to study many more phagosomes containing different fungi, bacteria, or other nonmicrobial materials.

“We aim to uncover more mechanisms related to how we defend ourselves against infection and uncover how autoimmunity and anti-tumor immunity are regulated,” Underhill said. “We are also keen to collaborate with and provide technical support to those interested in using the PhagoPL technique to address scientific questions.”

Other Cedars-Sinai investigators involved in the study include Avradip Chatterjee, Chen Qian, Katherine Lagree, Yang Wang, Courtney A. Becker, Michael R. Freeman, Ramachandran Murali, and Wei Yang.

This work was supported by National Institutes of Health grant R01AI071116 (DMU).

Read more on the Cedars-Sinai Blog: Meet David Underhill, PhD

“We identified a new subtype of cells surrounding therapy-resistant soft tissue sarcomas,” said Jlenia Guarnerio, PhD, a research scientist at Cedars-Sinai Cancer and senior author of the study. “These cells secrete a molecular ‘Velcro’ called CXCL16 that traps immune cells, especially T cells, and keeps them from entering the tumor. With very few T cells inside the tumor, available immunotherapies aren’t effective.”

Soft tissue sarcomas originate in muscle, fat, blood vessels, nerves, tendons and joint lining, and can occur anywhere in the body. Some of these tumors do not respond to immunotherapy, which helps the body’s own immune system fight cancer cells, said Marina Broz, a PhD student in the Guarnerio Lab at Cedars-Sinai and first author of the study.

“Previous studies have shown that cells called cancer-associated fibroblasts prevent immune cells from entering these tumors, leading to therapy resistance, but the way they achieve this is poorly understood in many cancers and particularly in soft tissue sarcomas,” Broz said.

Investigators found a particular subtype of cancer-associated fibroblasts surrounding therapy-resistant soft tissue sarcomas in laboratory mice.

“These are the cells that are trapping T cells outside the tumors,” Broz said. “And we noted that they rely on glucose to make energy, which turned out to be the key to turning non-responding tumors into responders.”

When investigators treated the mice with a glycolysis inhibitor to stop the cells from using glucose, the fibroblasts no longer secreted CXCL16—and T cells invaded the previously therapy-resistant tumors. This dramatically improved the abundance of T cells, thus making the tumors more vulnerable to chemotherapy as well.

“Without the inhibitor, the tumors were barely responsive to therapy,” Guarnerio said. “The inhibitor alone didn’t reduce tumor growth at all, but in combination with chemotherapy it significantly reduced tumor growth.”

Because glycolysis inhibitors aren’t safe for patients, investigators will work to develop a therapy to target CXCL16, said Guarnerio, who is also an assistant professor of Radiation Oncology and Biomedical Sciences at Cedars-Sinai.

“Targeting CXCL16 could also improve outcomes for patients with other types of immunotherapy-resistant tumors,” Guarnerio said. “We would like to see if we can engineer a therapy to improve treatment response in all tumor types with poor T cell infiltration.”

Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Distinguished Chair, said that the study is an example of translational research that may produce targeted therapies.

“This work represents our commitment at Cedars-Sinai Cancer to the promise of precision medicine, which may produce targeted therapies and further enhances our clinical adult and pediatric sarcoma program,” Theodorescu said.

Additional Cedars-Sinai authors participating in this study included Emily Y. Ko, Kristin Ishaya, Jinfen Xiao, Marco De Simone, Xen Ping Hoi, Roberta Piras, Basia Gala, Fernando H. G. Tessaro, and Anja Karlstaedt.

Other authors included Sandra Orsulic, Amanda W. Lund, and Keith Syson Chan.

Funding: J.G. was supported by the K99/R00 grant (CA212200) and R01 (CA258265) for the execution of this work. Additionally, J.G. was supported by grants from the Sarcoma Foundation of America (Grant 2019 SFA 15–19), and the Cedars-Sinai Cancer Accelerator Award. M.B. was supported by a National Cancer Institute F31 fellowship (1F31CA284888). K.S.C was supported by R01CA175397, R01CA175397-Supplement, U54CA274375. X.P.H received funding from U54CA274375. A.W.L. received support from the Cancer Research Institute (Lloyd J. Old STAR Award). A.K. was supported by the National Heart, Lung and Blood Institute (R00 HL141702) and the Leukemia Research Foundation New Investigator Award (Grant No. 941997).

Read more on the Cedars-Sinai Blog: Immunotherapy – The Fourth Pillar of Cancer Care

Using spatial analysis of tissue samples, Cedars-Sinai investigators have identified patterns that could predict whether patients with the most common type of ovarian cancer will experience early relapse after treatment. These patterns, detailed in a study published in the peer-reviewed journal

“Using spatial protein analysis, we looked not only at the types of cells within and around a tumor, but also at their relative positions and how they interact,” said Alex Xu, PhD, a research scientist at Cedars-Sinai Cancer and the Board of Governors Regenerative Medicine Institute at Cedars-Sinai and first author of the study.

Investigators’ analysis of ovarian cancer tissue samples identified patterns consistently associated with patients whose cancer relapsed soon after treatment, Xu said.

“Spatial analysis is the next frontier in tissue biomarker development and our group has demonstrated the importance of spatial analysis in several cancer types,” said Akil Merchant, MD, a senior author of the study and director of the Spatial Molecular Profiling Core facility at Cedars-Sinai Cancer.

High-grade serous ovarian carcinoma is the deadliest form of ovarian cancer, and ovarian cancers are particularly challenging because they are difficult to detect, Xu said. Frequently, patients with these tumors respond to initial treatment with surgery and chemotherapy but the cancer recurs.

In this study, investigators looked at tissue samples from 42 patients who had ovarian cancer—both primary tumors and tumors that recurred after patients’ initial treatment—using a technology called imaging mass cytometry, which reveals the spatial protein content of the tissue. The investigators’ main findings centered around plasma cells, a crucial part of the tumor immune response.

“Our findings suggest that plasma cells are a clinically important factor determining a patient’s time to relapse,” Xu said. “Previous research into their role has been contradictory, with some studies suggesting their presence predicted negative outcomes while others suggested positive outcomes.”

Here investigators found that outcomes were associated with the location of the plasma cells, and their relationship to adjacent cells types.

“Plasma cells were associated with good patient outcomes when lymphoid aggregates, which are structures that include T and B cells, were also abundant in the area immediately surrounding the tumor,” Xu said. “This could be because the plasma cells were part of these organized structures that facilitated communication between these immune cells, thus improving their ability to attack the tumor.”

Plasma cells were linked with poor patient outcomes when cells called cancer-associated fibroblasts, which are known to interfere with the activity of immune cells, were plentiful, which suggested that fibroblasts may be preventing plasma cells from communicating with other immune cells.  

“These different microenvironments could account for sometimes differing reports about the role of plasma cells in patient prognosis,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Distinguished Chair. “This avenue of investigation could help us identify biomarkers, or even precision therapies, that improve outcomes for patients with this particularly deadly cancer.”

Other Cedars-Sinai authors participating in the study include Marcela Haro and Ann E. Walts.

Additional authors participating in the study include Ye Hu, Joshi John, Beth Y. Karlan, and Sandra Orsulic.

Funding: SO was supported by the NIH grant R01 CA208753, the United States Department of Veterans Affairs Merit Awards VA-ORD I01 BX004974 and I01 BX006020, the Office of the Assistant Secretary of Defense for Health Affairs through the Ovarian Cancer Research Program Award No. W81XWH2210631, and the Sandy Rollman Ovarian Cancer Foundation. SO and AMX were supported by the NIH National Center for Advancing Translational Science (NCATS) UCLA CTSI Grant Number UL1TR001881.

Read more on the Cedars-Sinai Blog: Ovarian Cancer—The Whispering Cancer

Multiple sclerosis is a disease of the brain and spinal cord in which the body’s immune system attacks the protective sheaths that surround nerves, disrupting communication between the brain and the rest of the body. Brain imaging, which allows physicians to see the lesions that form at the point of attack, is essential for diagnosing the condition and guiding patient treatment.

Sicotte and Sati are among co-authors of a consensus statement from the North American Imaging in MS Cooperative that seeks to standardize imaging techniques for identifying chronic active lesions, an important indicator of chronic brain inflammation in MS. The statement, published in the peer-reviewed journal Brain, is designed to set guidelines for imaging chronic active lesions and how imaging will be used for diagnosis, predicting patient outcomes, and clinical trials.

They recently spoke with the Cedars-Sinai Newsroom about the role of imaging in MS today and in the future.

How has imaging changed treatment for patients with MS?

Sicotte: When I started treating patients with MS more than two decades ago, there were essentially no treatments, and now we have more than 25. One of the reasons we have these medications is because of advancements in the use of MRI to track disease activity in the brain and spinal cord of people who have MS. Because MRI is more sensitive than clinical attacks, it became a powerful tool to test the effectiveness of new therapies, and that energized research and led to the development of a whole suite of new MS treatments that decrease the likelihood of new lesions appearing.

How do lesions appear on an MRI?

Sicotte: In patients with active MS, the blood-brain barrier, which keeps potentially harmful substances from reaching the brain, breaks down due to immune activation. This results in what we call a contrast-enhancing lesion, the classic acute inflammatory lesion. These lesions show up as bright spots that are easily detected using MRI after injection of contrast. Over time, the blood-brain barrier repairs itself and leaves behind a chronic lesion that is akin to a scar that can also be tracked over time using dedicated MRI techniques.

What are the newest lesions that have been identified?

Sati: We and others have recently identified a new type of lesion, called a paramagnetic rim lesion, that we think is an indicator of chronic brain inflammation that may be the primary driver of disease progression in treated patients who do not have acute inflammatory lesions.

In paramagnetic rim lesions, microglia, the primary immune cells that respond to tissue injury and clean up debris in the brain, form a rim around lesions where the blood-brain barrier has healed. This is a sign that the inflammation is persisting at low intensity behind a closed blood-brain barrier. The rims are like a smoldering fire that continues to burn and slowly propagate. MS patients with a lot of paramagnetic rim lesions are more likely to have increased disability, so we think the lesions might be a good biomarker for progressive disease. Because our current therapies can’t cross a closed blood-brain barrier, we don’t have a way to treat these lesions at present.

Can advanced imaging techniques help identify therapies to treat chronic inflammation in MS patients?

Sati: We think so! We have received funding from the National Multiple Sclerosis Society and the National Institutes of Health to evaluate paramagnetic rim lesions as a diagnostic biomarker using detection techniques we developed. We are now exploring novel techniques to measure the amount of chronic inflammation and tissue damage in these lesions to evaluate the effects of new brain-penetrant therapies. We hope that these new quantitative techniques combined with AI will enable us to measure paramagnetic rim lesions in a fast, efficient way that could be put into practice in most imaging facilities and be deployed in clinical trials.

We’re doing this work in collaboration with all the stakeholders: the MRI physicists at our institution, the MRI vendors that provide the scanners and imaging technology, the neuroradiologists who read these scans, and the pharmaceutical industry that develops the therapies. We hope to prove that our concepts can be applied on different MRI scanners, so that they can be used in international clinical trials testing new therapies that can target these lesions and change the course of the disease.

What are your hopes for the future of MS care?

Sicotte: We're really lucky here at Cedars-Sinai. We have a large group of patients who are eager to participate in research, and we have been collecting MRI data over many years. Added to that, we're employing these newer techniques. We're hoping that the data we are collecting will tell us more about the drivers of progressive disease, how to predict which patients might not require treatment, and which we should treat aggressively from the outset.

Read more on the Cedars-Sinai Blog: Cedars-Sinai Neurology Chair Honored by National MS Society for COVID-19 Work

A recent study published in Frontiers in Immunology offers broader insight into the protein networks that allow immune cells to respond to harmful substances. This discovery could lead to treatments that leverage the body’s natural healing processes.

“This study demonstrates enormous potential for exploiting the natural immune process to better fight disease,” said Maya Koronyo-Hamaoui, PhD, a professor of Neurosurgery and Biomedical Sciences at Cedars-Sinai and senior author of the study. “White blood cells—which we studied here in the context of Alzheimer’s disease—are one of the first lines of defense against a variety of foreign and internal threats and are key for regulating tissue repair and maintenance.”

The study demonstrates the significance of osteopontin (OPN), a protein expressed by macrophages, a type of white blood cell that surrounds and destroys harmful organisms and clears cell debris and the buildup of abnormal proteins. Investigators, in collaboration with the Van Eyk Research Lab at Cedars-Sinai, concluded that OPN deficiency disrupts the balance of proteins in macrophages, eventually causing them to die.

“Macrophages clear toxic proteins, reduce inflammation, and help regenerate, rejuvenate, and encourage newly formed connections in the brain,” said Koronyo-Hamaoui.

The study builds on two previous studies from the Koronyo-Hamaoui Llab—published in Brain Behavior and Immunity and Brain—detailing the critical role played by bone-marrow derived macrophages and OPN expressed in macrophages in clearing Alzheimer’s disease-related amyloid-beta peptides and supporting central nervous system repair and regeneration.

“Our work supports further study into gene editing or immunotherapies that could have multifaceted impact,” said Altan Rentsendorj, PhD, a senior research associate in the Koronyo-Hamaoui Lab and first author of the study.

Investigators studied macrophages in laboratory mice. They compared normal cells, diseased cells treated with an FDA-approved multiple sclerosis treatment that caused them to overexpress OPN, and cells without the ability to produce OPN.

They found that diseased macrophages treated with the multiple sclerosis medication more effectively cleared amyloid-beta proteins and increased their anti-inflammatory activity. However, in cells without the ability to produce OPN, treatment with the multiple sclerosis medication did not restore normal protein expression.

Investigators also discovered that the presence of OPN is necessary to produce two other crucial anti-inflammatory molecules. Dysfunction of the first, ubiquitin C-terminal hydrolase L1, has been implicated in neurodegenerative diseases such as Alzheimer’s. The second, heme oxygenase 1, plays a critical role in preventing vascular inflammation.

“We were surprised to find that other neuroprotective proteins are dependent on OPN,” Rentsendorj said. “This work shows that OPN is critical for the machinery of rejuvenation in these innate immune cells.”

The Koronyo-Hamaoui Lab also recently published a review paper in Frontiers in Physiology synthesizing knowledge about angiotensin converting enzyme (ACE) and its role in Alzheimer’s disease. ACE, expressed by immune cells, degrades amyloid-beta and improves immune response.

The review outlines findings from 1975 onward, including numerous studies from the Koronyo-Hamaoui Lab in collaboration with the Bernstein Lab at Cedars-Sinai.

Significant among these are a 2020 paper published in Brain, which demonstrated that overexpression of ACE enhances the ability of white blood cells called monocytes to rid the body of toxic forms of amyloid-beta oligomers and fibrils, and a 2014 paper published in The Journal of Clinical Investigation. The review also notes that an analysis of human genome sequencing found people with a genetic variant that leads to lower expression of ACE in their blood had higher risk for Alzheimer's disease.

“This review builds a strong case for targeting monocytes and ACE in Alzheimer's disease,” said neurology fellow Ron Danziger, MD, first author of the review paper. “In extensive studies by the Koronyo-Hamaoui and Bernstein labs, we have consistently found an amazing effect of ACE on the characteristics of macrophages in the context of Alzheimer’s disease.”

Taken together, the new papers support the need for further research into therapies that might leverage immune function in blood or bone marrow cells to fight neurodegenerative disease.

“We need a much more effective treatment to address many aspects of Alzheimer’s disease,” said Keith L. Black, MD, chair of the Department of Neurosurgery, the Ruth and Lawrence Harvey Chair in Neuroscience at Cedars-Sinai, and co-author of both studies. “Genetically manipulating monocytes to enhance ACE or OPN, which would target more than plaque clearance, could be a very promising technique.”

Funding: The study appearing in Frontiers in Immunology was funded by the National Institute on Aging of the National Institutes of Health (grant numbers R01AG056478, R01AG055865, AG056478-04S1 and R01AG075998) and the Tom Gordon, Haim Saban and Wilstein foundations.

The study appearing in Frontiers in Physiology was supported by the National Institute on Aging of the National Institutes of Health (grant numbers R01AG055865, R01AG056478, R01AG075998 and R01AG042195); a BrightFocus Foundation Award; The Coins for Alzheimer’s Research Trust (CART) Fund; the Cedars-Sinai Jona Goldrich Center for Alzheimer’s and Memory Disorders; the Saban, Gordon, Marciano and Wilstein private foundations; and the National Center for Advancing Translational Sciences (CTSI grant UL1TR000124).

Read more from the Cedars-Sinai Blog: How to Help a Loved One With Alzheimer’s or Dementia

The study, published today in the leading scientific journal Nature, found that loss of the Y chromosome helps cancer cells evade the body’s immune system. This common impact of the aging process in men results in aggressive bladder cancer, but somehow also renders the disease more vulnerable—and responsive—to a standard treatment called immune checkpoint inhibitors.

Based on their research, investigators are developing a test for loss of the Y chromosome in tumors with the goal of helping clinicians tailor immune checkpoint inhibitor treatment for male patients with bladder cancer.

“This study for the first time makes a connection that has never been made before between loss of the Y chromosome and the immune system’s response to cancer,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer, the PHASE ONE Distinguished Chair and corresponding author of the publication, who initiated the research. “We discovered that loss of the Y chromosome allows bladder cancer cells to elude the immune system and grow very aggressively.”

Lead collaborators on the study also included Johanna Schafer, a postdoctoral fellow, and Zihai Li, MD, PhD, medical oncologist and immunologist, both at The Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute.

In humans, each cell normally has one pair of sex chromosomes; men have one X and one Y chromosome, while women have two X chromosomes. In men, loss of the Y chromosome has been observed in several cancer types, including 10%-40% of bladder cancers. Loss of the Y chromosome also has been associated with heart disease and Alzheimer’s disease.

The Y chromosome contains the blueprints for certain genes. Based on the way these genes are expressed in normal cells in the bladder lining, investigators developed a scoring system to measure loss of the Y chromosome in cancers.  

The investigators then reviewed data on two groups of men. One group had muscle invasive bladder cancer and had their bladders removed, but were not treated with an immune checkpoint inhibitor. The other group participated in a clinical trial and were treated with an immune checkpoint inhibitor. They found that patients with loss of the Y chromosome had poorer prognosis in the first group and much better overall survival rates in the latter.

To determine why this happens, investigators next compared growth rates of bladder cancer cells from laboratory mice.

The investigators grew cancer cells in a dish where the cells were not exposed to immune cells. The researchers also grew the diseased cells in mice that were missing a type of immune cell called T-cells. In both cases, tumors with and without the Y chromosome grew at the same rate.

In mice with intact immune systems, tumors lacking the Y chromosome grew at a much faster rate than did tumors with the intact Y chromosome.

“The fact that we only see a difference in growth rate when the immune system is in play is the key to the ‘loss-of-Y’ effect in bladder cancer,” Theodorescu said. “These results imply that when cells lose the Y chromosome, they exhaust T-cells. And without T-cells to fight the cancer, the tumor grows aggressively.”

Based on their results derived from human patients and laboratory mice, Theodorescu and his team also concluded that tumors missing the Y chromosome, while more aggressive, were also more vulnerable and responsive to immune checkpoint inhibitors. This therapy, one of the two mainstay bladder cancer treatments available to patients today, reverses T-cell exhaustion and allows the body’s immune system to fight the cancer.

"Fortunately, this aggressive cancer has an Achilles’ heel, in that it is more sensitive than cancers with an intact Y chromosome to immune checkpoint inhibitors,” said Hany Abdel-Hafiz, PhD, associate professor at Cedars-Sinai Cancer and co-first author of the study with Schafer and Xingyu Chen, a research bioinformatician at Cedars-Sinai.

Preliminary data not yet published shows that loss of the Y chromosome also renders prostate cancers more aggressive, Theodorescu said.

“Our investigators postulate that loss of the Y chromosome is an adaptive strategy that tumor cells have developed to evade the immune system and survive in multiple organs,” said Shlomo Melmed, MB, ChB, executive vice president of Academic Affairs and dean of the Medical Faculty at Cedars-Sinai. “This exciting advance adds to our basic understanding of cancer biology and could have far-reaching implications for cancer treatment going forward.”

Further work is needed to help investigators understand the genetic connection between loss of the Y chromosome and T-cell exhaustion.

“If we could understand those mechanics, we could prevent T-cell exhaustion,” Theodorescu said. “T-cell exhaustion can be partially reversed with checkpoint inhibitors, but if we could stop it from happening in the first place, there is much potential to improve outcomes for patients.”

While women do not have a Y chromosome, Theodorescu said these findings could have implications for them as well. The Y chromosome contains a set of related genes, called paralogue genes, on the X chromosome, and these might play a role in both women and in men. Additional research is needed to determine what that role might be.

“Awareness of the significance of Y chromosome loss will stimulate discussions about the importance of considering sex as a variable in all scientific research in human biology,” Theodorescu said. “The fundamental new knowledge we provide here may explain why certain cancers are worse in either men or women, and how best to treat them. It also illustrates that the Y chromosome does more than determine human biologic sex.”

Funding: This work was supported in part by National Institutes of Health grant numbers P01CA278732, R01CA143971, R01CA262069, R01CA262388 and R01AI077283; an Ohio State University Comprehensive Cancer Center Tumor Immunology T32 post-doctoral fellowship award, and the Immune Monitoring and Discovery Platform and the Pelotonia Institute for Immuno-Oncology at OSU Comprehensive Cancer Center.

DOI: 10.1038/s41586-023-06234-x

Read more on the Cedars-Sinai Blog: Bladder Cancer Breakthroughs

Specifically, the investigators have improved understanding of the steps that lead to the production of IL-1 beta, a potent inflammatory protein signal released during many inflammatory responses.

“We now have a clearer understanding of the stepwise process that leads to the production of IL-1 beta,” said Andrea Wolf, PhD, assistant professor of Biomedical Sciences and Medicine at Cedars-Sinai, and a senior and corresponding author on the new study. “By understanding the process, we hope to one day find a treatment for diseases associated with this inflammatory response.”

When the innate immune system—the defense system we were born with—identifies a potentially harmful bacterium, virus, or other external invader, it unleashes white blood cells to surround and attack the foreign agent. This can cause swelling, redness, heat and pain in the body’s tissues that—in a healthy body—eventually go away.

Some people, however, get stuck in the inflammation phase. This causes what is known as chronic inflammation. Chronic inflammation can damage healthy cells in the body and is thought to lead to serious conditions like Type 2 diabetes, heart disease and depression.

“Inflammation, in many instances, is vital to a thriving immune system and healthy body,” said David Underhill, PhD, chair of the Department of Biomedical Sciences and the Janis and William Wetsman Family Chair in Inflammatory Bowel Disease, who is also a senior and corresponding author on the study. “However, prolonged inflammation can wreak havoc on the body. This underscores the importance of understanding the cellular process of how inflammation is activated so we can work toward finding new treatments to curb chronic inflammation.”

The study published today is a follow-up to Cedars-Sinai research published in 2016 that explains how cells act to detect an infection. In that study, investigators discovered that an enzyme called hexokinase, typically used by cells to convert glucose into energy, has a second, inflammatory function. They discovered that hexokinase binds to a sugar from the cell wall of bacteria and activates the inflammasomes, leading to the production of IL-1 beta. Inflammasomes are receptors of the innate immune system that recognize microbes and tissue damage.

The current work presents a more complete picture of this process.  

The investigators discovered that hexokinase leaves the mitochondria, the part of a cell that generates energy. This jump-starts an immune response: The release of hexokinase destabilizes the mitochondria and alerts the cell that something is wrong. This leads to clustering of a channel called VDAC in the membrane of the mitochondria, which interacts with another protein called NLRP3 to initiate inflammasome assembly. The inflammasomes then produce IL-1 beta, a driver of inflammation.

The investigators studied cells that were derived from laboratory mice to understand the steps involved in the IL-1 beta pathway. The team used substances called inhibitors that block cellular functions as well as gene-editing technology to turn off certain genes and the proteins they express. This allowed them to understand which proteins are vital to triggering inflammation.

Cedars-Sinai postdoctoral scientist Sung Hoon Baik, PhD, used the super-resolution microscope that is part of the Cedars-Sinai Biobank and Research Pathology Resource to visualize and measure the steps of this inflammatory process within individual cells.

“Being able to target specific steps in this pathway is vital, because in addition to being important for inflammation, the components of this pathway also play a vital role in maintaining energy within the cell,” Wolf said. “We want to home in on its inflammatory role, not just turn it all off, because that would be bad for the cell.”

The investigators are continuing to study the cellular steps leading up to, and resulting from, hexokinase’s role in the activation of inflammasomes. They are also using the results from this study to begin to target this inflammatory pathway in different diseases.

Other Cedars-Sinai investigators who worked on the study include Courtney Becker, manager of the Underhill Laboratory at Cedars-Sinai; Sarah Fett, research associate at Cedars-Sinai; and V. Krishnan Ramanujan, PhD, research associate professor in the Department of Medicine at Cedars-Sinai and director of the Cedars-Sinai Biobank.

Funding: The study was funded by the National Institutes of Health (award numbers R01AI148465, R01GM085796, R01AI071116).

Follow Cedars-Sinai Academic Medicine on Twitter for more on the latest basic science and clinical research from Cedars-Sinai.

Read more on the Cedars-Sinai Blog:  Autoimmune Diseases: When Your Body Turns On You