Radically different
Nature Medicine, Published online: 30 April 2026; doi:10.1038/s41591-026-04369-8
The alarming rise in the incidence of colorectal cancer among younger individuals is probably due to environmental factors; epigenetic signatures of exposures may help uncover drivers of this trend, but questions remain.
Nature Medicine, Published online: 30 April 2026; doi:10.1038/s41591-026-04353-2
OBSCORE is a machine learning-based risk prediction tool that uses a set of clinical features to stratify individuals with a body mass index (BMI) of ≥ 27 kg m−2 by their 10-year risk of obesity-related complications, outperforming existing models. OBSCORE is generalizable across diverse populations, supporting risk-based prioritization of obesity interventions that goes beyond simple BMI thresholds.
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Body mass index has its limitations, but for now it’s the metric medicine often defaults to when predicting weight-related health problems. A new tool promises to better define who’s at risk for obesity complications, based on measures that include BMI but also family history, diet, current illness, and socioeconomic factors culled from medical records.
One aim of the research is to better understand who’s a candidate for an obesity drug, often prescribed based on BMI alone or BMI in combination with another disease. Over time, GLP-1 medications, whose initial target was type 2 diabetes, have revealed their power to ease cardiovascular disease, kidney disease, liver disease, sleep apnea, and osteoarthritis, in addition to promoting significant weight loss. But discerning who’s the best fit for the costly, lifelong treatment has been uncertain.
“We really wanted to have an integrated model that enables us to look at not one, but 18 different obesity-relevant complications,” Claudia Langenberg, co-author of a study about the new model published Thursday in Nature Medicine, said in a media briefing Tuesday. She is director and professor of medicine and population health at Precision Healthcare University Research Institute of Queen Mary University of London.
After months of anticipation, Supreme Court justices heard arguments about a long-standing tactic used by generic companies to carve out a distinct market for a medicine, and did not appear inclined to alter legal standards for the maneuver.
At issue is skinny labeling, which refers to moves by generic companies that seek regulatory approval to market a drug for a specific use, but not other patented uses for which a brand-name medicine is prescribed. For instance, a generic drug could be marketed to treat one type of heart problem but not another. In doing so, the generic company seeks to avoid lawsuits claiming patent infringement.
This tactic has been a key tool for generic companies ever since the Hatch-Waxman Act was signed into law more than four decades ago. The law established the mechanisms by which generic drugs can more readily enter the marketplace. And skinny labeling is one way that Congress attempted to foster more competition and benefit consumers.
Background: Patients’ digital access to their personal health data is becoming increasingly common worldwide. However, medical documentation often contains technical language and sensitive information, which can lead to potential misunderstandings and distress among patients. These issues may be particularly impactful in mental health contexts. Large language models (LLMs) offer a promising approach by transforming clinician-generated health notes into language that is more patient-centered, nonmedicalized, and empathetic. However, risks related to accuracy and clinical safety have not been adequately investigated in psychiatry. Objective: This study aimed to qualitatively analyze the errors introduced by LLMs when transforming notes written by psychiatrists into patient-facing formats. It also highlights the implications for clinical communication and patient safety. Methods: Clinical notes (n=63) written by 19 psychiatrists in an outpatient treatment setting were collected, anonymized, and translated from German to English by humans. OpenAI GPT-3.5 Turbo was used to develop a preprompt that transformed these notes into a patient-centered, lay-readable form through an iterative process. Three psychiatrists qualitatively analyzed the LLM-revised documentation using Kuckartz content analysis. They compared the preconversion and postconversion notes to systematically identify and categorize LLM-induced errors. Results: Five categories of clinically relevant errors were identified: (1) clinical misinterpretations, particularly in critical assessments such as suicidality, where nuanced terminology was oversimplified or inaccurately represented; (2) attribution errors, where behaviors or roles within family dynamics or interactions were incorrectly attributed to different individuals; (3) content distortion errors, which were characterized by speculative additions, emotional exaggerations, and inappropriate contextual assumptions; (4) abbreviation and terminology errors, which resulted from inaccurate expansions of medical abbreviations and terms; and (5) structural and syntax errors, which resulted in ambiguity, particularly when the original notes were brief or bulleted. Despite significant improvements in the readability and overall linguistic fluency of the converted notes, these errors occurred. Conclusions: LLMs have the potential to transform psychiatric notes into patient-friendly formats. However, critical errors remain prevalent and can impair clinical judgment, understanding of patient circumstances, clarity of medication regimens, and interpretation of clinical observations. To safely integrate artificial intelligence–generated documentation into psychiatric care, clinician oversight and targeted model refinement are essential. Future research should explore strategies to mitigate these errors, assess their comprehensive clinical impact, and incorporate patient and provider perspectives to ensure robust implementation.
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SAN DIEGO, CA – At the 2026 American Association for Cancer Research (AACR) Annual Meeting, Verismo Therapeutics unveiled early data that could reshape CAR T-cell design. Built on a novel “KIR-CAR” platform, the experimental therapy SynKIR-310 uses a multi-chain, split-signaling architecture that mimics natural immune receptors, enabling T cells to stay active through repeated tumor attacks while potentially reducing exhaustion and safety risks that have long limited conventional approaches.
In preclinical studies, SynKIR-310 delivered potent anti-tumor responses in B-cell cancer models, including 100% survival in treated mice. The therapy targets CD19 using a canine-derived binding domain and is now being tested in patients with relapsed or refractory B-cell non-Hodgkin lymphoma in the Phase I CELESTIAL-301 trial.
Early clinical findings included a 70-year-old patient with follicular lymphoma who achieved a complete response just 28 days after receiving the lowest dose, an outcome still holding at six months. While preliminary, the results suggest that reengineering CAR T-cell biology itself may unlock more durable responses with fewer toxic side effects, tackling two of the field’s toughest challenges.
Verismo’s presentation of the data at AACR itself was understated, unfolding among rows of posters and quiet conversations. In the eyes of Laura A. Johnson, PhD, it was the culmination of a nearly two-decade-long scientific journey. It all began as a postdoc in the lab of immunotherapy trailblazer Steve Rosenberg, MD, PhD, who is currently chief of surgery at the National Cancer Institute, among several other appointments.
Johnson, who is chief scientific officer and chief operating officer at Verismo, told Inside Precision Medicine, “My postdoc project was literally taking, finding, and choosing an antigen; finding a shared antigen T cell receptor; subcloning it; and making it into a T cell. Not a CAR drug, but a TCR engineered drug that worked so well in the first year that they used to have money on tap there, turned it into a clinical trial, and then put me as an academic in charge of overseeing the clinical trial, the making of the drug, and getting to go and visit and shake the patient’s hands. In the four years since then, we saw literally pounds of tumor fall off these patients when we visited them in the clinic.”
That dramatic and deeply personal experience showed Johnson the promise and limitations of immune-based cancer therapies. Even as she saw tumors regress in ways that seemed almost implausible, she saw that those responses were not universal or durable and that toxicity could complicate even the most striking successes.
She continued to gain experience and try out different things, eventually leading her to the University of Pennsylvania (UPenn) with CAR T-cell therapy pioneer Carl June, MD. Working with June at UPenn, Johnson expanded CAR T-cell research rapidly, supported by industry investment and a mandate to investigate engineered immune cells’ effects on a variety of cancers. It was during those “great five years” that Johnson began to tackle solid tumors with CARs. Even as the field struggled with relapse, toxicity, and solid tumor efficacy, she led the way in clinically implementing experimental therapies.
Johnson’s subsequent move into industry, including a leadership role at GlaxoSmithKline (GSK), broadened her perspective further. “At the time, I did not see myself as an industry kind of person,” said Johnson. “I didn’t know what that was, but I did go to GSK for five years. It was amazing. I learned so much there. You know how to run clinical trials across the globe for registration. These huge teams of support. It was great.”
Johnson added, “I also had a sponsored research agreement with GSK, which was then exploring cell therapy, and after a year of that, they decided to open up a whole cell therapy unit and invited me to come and lead the group.”
By the time she returned to academic collaborations, she had seen the field from multiple angles—scientific, clinical, and operational—and had developed a growing sense that the limitations of CAR T therapy might be rooted in something more fundamental than incremental improvements could fix.
That realization sharpened when she reconnected with colleagues at UPenn, including Carl June and Michael Milone, PhD, MD, the co-inventors of Kymriah, the first-ever approved CAR T, who had already begun questioning the underlying design of conventional CAR T systems. “Back then, Mike and Carl already saw that it worked, but they felt something was not right about it. You know that patients can have recurrences of cancer, and it doesn’t work in solid tumors, no matter what they do. So they were already in the background trying to tinker and figure it out.”
The success of Kymriah had proven that engineered immune cells could be transformative, but it had also exposed persistent problems that could not be ignored. “At the time, Mike had a great idea that the artificiality of the single-chain CAR T was causing these problems because it was not evolutionarily selected for. It’s not natural. Maybe this has something to do with it.”
That insight led Milone to revisit the basic biology of immune receptors, examining how natural systems separate recognition from activation rather than fusing them into a single, continuously active structure. “They all have the same receptor format to bind to the target on the cell’s outside. The receptor is anchored in place by a neck in the cell membrane, while a completely separate internal signaling mechanism is also anchored by a neck in the membrane and is activated from the inside. And these two actually don’t interact. They have nothing to do with each other unless and until that target is found unbound, which brings the two together.”
From this observation emerged the concept of KIR-CAR, a multi-chain system inspired by natural killer (NK) cell biology that attempts to restore a more controlled and conditional activation process. “T cells, their main job, is actually not to kill you but rather to kill bad things, so they try and shut everything down,” Johnson explained. “So, we said, ‘Let’s use NK cells.’ They’re the other main lymphocyte that attacks tumors, and they’re innate. Maybe they won’t have the same problems with shutting down. Let’s throw it at the wall and see what sticks.’”
The resulting design combined elements of NK cell receptors with T-cell machinery, creating what Johnson describes as a more natural on-off switch. The combination of the killer immunoglobulin receptor (KIR), which acts as the outside binder, with existing intracellular signaling machinery used for CARs resulted in the name KIR-CAR. “A chimera has the head of a lion, the body of a goat, and the tail of a snake,” said Johnson, using the hybrid from Greek mythology in describing a traditional CAR. “We’ve un-Frankensteined them and put them back. What we end up with is just a more natural on/off switch. Why would we think we can do better than a million years of evolution at figuring out a way to trigger and turn off these cells to get rid of bad things?”
In early preclinical experiments, KIR-CAR cells were compared to single-chain CAR T cells, showing subtle differences in vitro but greater differences in complex systems. By the time Johnson presented SynKIR-310 at AACR, those differences had become a consistent pattern across preclinical studies and early clinical observations, suggesting that the KIR-CAR approach may improve tumor control without the toxicity of conventional CAR T therapies.
Johnson said, “It’s been surprising, but great news. Our preclinical team has reversed the process, gone back to mice, and successfully reproduced the same findings. Not only is the KIR-CAR superior at eliminating tumors, but it also has a shorter duration of interferon gamma. In contrast, the single-chain CAR T cells that everyone else on the planet is using appear to be frighteningly toxic because they go off script.”
Johnson vividly described that uncontrolled activation. “If you do any assay with them, presumably including in vivo, lasting more than a day, they start killing everything around them,” she said. “They start spitting out interferon gamma. They infect every cell they come into contact with; they proliferate; they produce cytokines; they cause lysis; and they have many other harmful off-target effects.”
That behavior aligns with her broader description of how conventional CAR T cells can become overactivated and exhausted. Johnson elaborated, “The CAR T cell is hyperactivated, and it’s going down. It knows it’s exhausted, but it also detects an activated state, so it sets off fireworks and hopes the grenade response will take out whatever is bad too.”
In contrast, biomarker data from SynKIR-310 suggest a more controlled and physiologic immune response. “When we look at the biomarkers, they’re not making a ton of interferon or TNF alpha,” said Johnson. “Even from the first dose we used, we showed clearly biological activity where the T cells go in; as of day seven, you start to see interferon pickup. It peaks out at about ten days.”
Johnson continued, “Then it’s textbook as for how a T cell activates when it sees its target; this process is crucial for the immune response. It showed that it’s very clearly encountering a target, activating and doing what it’s supposed to do. However, the blood levels we observed were significantly lower than expected due to hematologic malignancies, which involve widespread tumors throughout the body, including the bone marrow and blood.”
Clinical observations, though limited, reinforce that pattern. “The results were announced today for the first nine patients. It’s a basket study for both ovarian cancer and cholangiocarcinoma. So, there are three very high unmet and urgent needs for patients. Most of these have one line of approved therapy, or maybe two, and once they become advanced refractory or metastatic, there’s nothing for these patients. Overall survival is measured in weeks, not months.”
Within that context, even modest responses carry significance. “Four of the nine showed measurable tumor reductions and the last patient treated, the last one in cohort three, had a response that continued past our data cutoff and keeps going. So, it’s very good news.”
Perhaps most striking, however, is the KIR-CAR’s apparent safety profile. “The biggest thing they were worried about is toxicity. Everybody knows that CAR causes cytokine release syndrome (CRS), and interferon gamma causes neuropathic disease, leading to brain damage and other severe symptoms. It’s got a bad rap. I think they got a headache one night that was called ‘CRS.’ That was gone the next morning. That’s it.”
For Johnson, the significance of these findings lies less in any single result than in their consistency across different models and targets, reinforcing her belief that the KIR-CAR platform reflects a fundamentally different—and potentially more effective—approach to engineering immune cells. “You can want something to work as much as you want, but if it doesn’t, it doesn’t, and you accept it,” said Johnson. “So it’s okay that the data was the same for both our platform assets, the CD19 and mesothelioma KIR-CARs; this result is real.”
That reproducibility has given her confidence to draw comparisons with existing therapies. “When we see the same things again, there are fewer CRS cytokines, less duration of toxicity, and way better treatment. It is better than both Kymriah and Yescarta. We did the in vivo models, but it’s a little better than Kymriah and a lot better than Yescarta.”
At the same time, she remains grounded in the understanding that these are early results, requiring validation in larger trials and over longer follow-up periods, even as they point toward a broader shift in how the field might approach the design of next-generation immunotherapies. Rather than continuing to build increasingly complex artificial systems, the KIR-CAR approach suggests that aligning more closely with the immune system’s natural architecture—its built-in checks, balances, and conditional activation mechanisms—may offer a path to therapies that are both more effective and less toxic.
That idea, rooted in the biology she has spent her career studying, connects her earliest experiences watching tumors disappear in clinical trials to the work she now presents. It formed a narrative for Johnson that is less about a single product than about a way of thinking: that progress in cancer immunotherapy may ultimately depend not on pushing the immune system harder but on understanding it more deeply and working within the logic it has evolved over millions of years to follow.
The post Die Hard: KIR-CAR T Cells Show Early Promise as Reliable Cancer Immunotherapy appeared first on Inside Precision Medicine.
Cases of bowel and ovarian cancer are rising, but only among people under 50, according to research published in the British Medical Journal Oncology today, April 28, 2026. While other types of cancer are also rising in older adults, this particular trend among younger adults is striking.
A key factor, the researchers’ work suggests, is excess weight. But that does not fully explain the trends they saw.
In particular, there was a significant rise in 11 cancers among the younger adults with known behavioral risk factors. These cancers were: thyroid, multiple myeloma, liver, kidney, gallbladder, bowel, pancreatic, womb lining (endometrial), mouth, breast, and ovarian cancers.
Rates of all these cancers also rose significantly among the older adults, with the notable exceptions of bowel and ovarian cancers.
Besides mouth cancer, all 11 cancers associated with known behavioral risks were linked to obesity. And six (liver, bowel, mouth, pancreas, kidney, and ovary) were also linked to smoking; four (liver, bowel, mouth, and breast) were associated with alcohol intake; three (bowel, breast, and endometrial) were linked to physical inactivity; and one (bowel) was associated with dietary factors.
“Of the 11 cancers we identified which were increasing and linked to known lifestyle factors—the most common by far in younger adults was breast cancer,” the study’s lead author, professor Montserrat Garcia-Closas, MD, DrPH, told Inside Precision Medicine. Garcia-Closas is in Integrative Cancer Epidemiology, Division of Genetics and Epidemiology, and The Cancer Epidemiology and Prevention Research Unit, The Institute of Cancer Research, London.
The rising incidence of certain cancers among people under 50 isn’t unique to England, and one major question is whether changes in behavioral risk factors might be to blame.
This research group analyzed cancer incidence trends in England from the National Disease Registry Service for the period 2001 to 2019, comparing patterns by sex in two age groups: 20–49 year olds and those aged 50+ for more than 20 different cancer types.
This database, “Captures virtually every cancer diagnosis in England going back decades—one of the most complete registries in the world. That scale is what allows us to track trends reliably across the whole population, not just a sample,” said Garcia-Closas.
The team used national health surveys to look at trends in established risk factors: smoking, alcohol intake; diet (high red/processed meat, low fiber intake), excess weight (BMI), and physical inactivity to quantify any changes by age and sex and estimate the proportion of cancers attributable to specific risk factors.
Their analysis showed that new cases of 16 out of 22 cancers in younger women, and 11 out of 21 cancers in younger men, increased significantly in England between 2001 and 2019.
And five cancers—endometrial, kidney, pancreatic, multiple myeloma, and thyroid cancer— increased significantly faster in younger than in older women, while multiple myeloma increased faster in younger than in older men.
But with the exception of excess weight, trends in these risk factors over the past one to two decades have been stable or improving for younger adults, with the largest reductions of around 7% in red meat consumption.
The average daily amount of red meat eaten, they report, fell from 38 grams in 2008 to 17 grams in 2018 among younger men, and from 22 grams to 10 grams in younger women. And average processed meat intake in younger women was half that of younger men: 10 grams versus around 20 grams. And while more than 90% of younger adults weren’t eating enough fiber in 2018, their intake remained stable or slightly improved in both sexes between 2009 and 2019. And these trends were similar in older adults.
Established behavioral risk factors accounted for a substantial share of cancer cases. In 2019 these contributed 68%–65% of mouth cancers for younger and older men, respectively; 42%–48% of liver cancers; 49%–53% of bowel cancers, 29%–33% of kidney cancers, and 36%–34% of pancreatic cancers.
Among women they accounted for 52%–45% of mouth cancers; 35%–42% of endometrial cancers; 44%–46% of liver cancers; 38%–42% of bowel cancers; 33%–37% of kidney cancers; 31%–28% of pancreatic cancers; and 19% to 24% of gallbladder cancers.
Excess weight was the risk factor associated with most cancers in 2019, ranging from 5% for ovarian cancer to 37% for endometrial cancers.
“These patterns suggest that while similar risk factors across ages are likely, some cancers may have age-specific exposures, susceptibilities, or differences in screening and detection practices,” write the researchers.
“Prevention takes a long time and we must act now with what we know, with better and more effective public health policy and programs to address the overweight and obesity epidemic,” said Garcia-Closas.
The post Bowel and Ovarian Cancer Cases Rise Among U.K. Young Adults appeared first on Inside Precision Medicine.
As cancer survival rates improve, a new challenge is coming into sharper focus: what happens after the first cancer is treated. A large population-based study drawing on decades of U.S. registry data offers one of the most comprehensive looks yet at the risk of subsequent primary cancers (SPCs)—and reveals a complex, evolving landscape shaped by age, sex, and generational exposure. The work was published in PLOS Medicine.
Using data from more than 3.3 million individuals diagnosed with a first primary cancer between 1975 and 2019, investigators from the Virginia Commonwealth University (VCU) School of Medicine analyzed nearly 30 million person-years of follow-up, identifying more than 510,000 second cancers. Their findings, based on Surveillance, Epidemiology, and End Results (SEER) registries, show that SPC risk is not static but varies significantly depending on when patients were born, how old they were at diagnosis, and the type of cancer they initially had.
“We have follow-up guidelines after treatment for the primary cancer, but we don’t really know what risk profile these patients fall into for another cancer,” said Susan Hong, MD, who co-directs a cancer survivorship outcomes research program at VCU and co-directed the study. “They’re not average-risk individuals—but they’re not necessarily at extremely high risk across the board either. That’s where it becomes very nuanced and complex.”
The analysis confirmed that SPC incidence increases with age at first cancer diagnosis, rising substantially in both men and women, though more steeply in males. Among women, rates climbed from 915 per 100,000 person-years at ages 35–39 to 1,980 at ages 75–79; in men, the increase was from 1,228 to 2,945.
But these patterns were not consistent across all cancer types. For breast cancer survivors, the risk of developing a second cancer remained relatively stable regardless of age at diagnosis—a finding that surprised the investigators.
“I was kind of surprised that the risk of subsequent cancer didn’t vary by age among breast cancer survivors,” said Hui Cheng, PhD, the study’s lead analyst. “I thought older patients would have higher risk, but that wasn’t necessarily the case.”
By contrast, survivors of lung and bladder cancers and melanoma showed a clear age-related increase in SPC risk, suggesting that surveillance strategies may need to differ significantly by index cancer type.
One of the study’s most striking findings emerged from its age–period–cohort modeling: SPC risk peaked among individuals born between 1935 and 1945, then declined in more recent birth cohorts—with notable exceptions.
Researchers observed rising risks among female lung cancer survivors and male bladder cancer survivors, even as overall SPC incidence declined in more recent decades. The cohort-specific patterns hint at underlying environmental or behavioral exposures that vary across generations.
“We observed higher risk in cohorts born in the ’40s and ’50s,” Cheng said. “If we think back, those individuals were young adults during peak tobacco use, which may be a contributing factor. But we don’t have individual-level smoking data, so we can’t confirm that directly.”
This limitation underscores a key challenge of large registry-based studies: while they offer statistical power and long-term follow-up, they often lack granular data on treatment exposures, genetics, and lifestyle factors.
The findings also reflect the dual-edged nature of cancer treatment progress. As therapies improve and patients live longer, the window for developing late effects—including second malignancies—widens.
“We’re doing so well treating primary cancers, and people are living longer,” Hong said. “But we also need to think about what risk profile these patients fall into over time.”
Radiation therapy and certain chemotherapies are known contributors to secondary malignancies, with risks often emerging 10 to 15 years after exposure. Yet without detailed treatment data, the current analysis cannot disentangle these effects.
Instead, the study serves as what investigators describe as a “hypothesis-generating” effort—mapping broad patterns that can guide more targeted research.
“We’re trying to figure out how to risk-stratify patients and pay attention to their long-term health care needs without overreacting or underreacting,” Hong said.
In practice, that could mean more intensive surveillance for older survivors of certain cancers, while maintaining consistent monitoring across age groups for others, such as breast cancer.
The findings also highlight gaps in the current survivorship infrastructure—particularly for adult-onset cancers. While pediatric oncology has long benefited from coordinated long-term follow-up systems, similar frameworks are less developed for adult survivors.
“There’s been a long-standing effort to follow childhood cancer survivors, but we don’t have that kind of system in place for adults,” Hong noted. “Now that we’re seeing more cancers in younger adults, we need to think about how to address decades of survivorship.”
Ultimately, the study raises as many questions as it answers. Why do certain cohorts carry higher risks? How do treatment regimens, genetics, and lifestyle interact to drive SPC development? And which risk factors are modifiable?
The research team is already looking ahead to studies that can incorporate more detailed patient-level data, with a focus on identifying actionable prevention strategies.
“We’re very interested in understanding what factors are associated with better or worse outcomes—especially modifiable risk factors,” Cheng said.
The post Who Gets a Second Cancer—and When? Large Study Reveals Complex Patterns appeared first on Inside Precision Medicine.
Weill Cornell Medicine researchers have defined new transcriptional and functional characteristics of Hodgkin and Reed-Sternberg (HRS) cells in classic Hodgkin lymphoma (cHL), detailing how malignant cells are the result of an arrested stage of B cell development. The research, published Blood Cancer Journal, shows that characteristics of HRS cells are incomplete plasma cell differentiation, robust unfolded protein response (UPR) activation, and coordinated immune evasion mechanisms that influence both T cells and natural killer (NK) cells.
“Hodgkin lymphoma is unique in that the tumor cells don’t form continuous sheets of tumor cells, but they are largely scattered within lymphoid tissues that are not cancerous,” senior author Ethel Cesarman, MD, PhD, pathologist at Weill Cornell Medicine told Inside Precision Medicine. “High proliferation or reduced cell death are not the predominant features of these cells. It is tumor of B cell origin, but unlike normal B cells that develop into plasma cells that produce antibodies but can no longer divide, the tumor cells of Hodgkin lymphoma are stuck in between.”
To define the molecular activity that leads to this arrested state, the researchers analyzed RNA sequencing data from 18 primary cHL tumors, four cHL cell lines, and matched intra-tumoral B cells. They then compared these data with 40 cases of primary mediastinal B cell lymphoma (PMBL).
The resulting data showed that HRS cells lose core B cell identity programs while simultaneously acquiring partial plasma cell-like gene expression. This reflects an “abortive plasma cell differentiation” process in which B cell development begins but is not completed. Normally, germinal center B cells transition into antibody-secreting plasma cells, but in cHL this process is interrupted, and immunoglobulin production is lost.
An important finding of this study was activation of the unfolded protein response (UPR) pathway, which is usually active in plasma cells to help manage the stress of high-volume antibody production. In HRS cells, however, immunoglobulin synthesis is absent. This mismatch appears to place the cells under chronic endoplasmic reticulum stress, which may then be redirected to serve as a survival mechanism.
The study also found that UPR-related genes, including XBP1, ATF6, and particularly PDIA6, were highly expressed in HRS cells. PDIA6 emerged as a potentially specific diagnostic marker. As Cesarman noted in her interview, Hodgkin lymphoma sometimes can be hard to diagnose. “A marker commonly used is CD30, but these may be expressed in other neoplastic and benign conditions, so PDIA6 may be a useful immunohistochemical marker for further differentiation,” she added.
This provides a new framework for understanding the role of UPR activation, which has not been widely implicated in prior models of Hodgkin lymphoma. Historically cHL research has focused on B cell receptor signaling defects, NF-κB activation, and immune checkpoint expression.
The team also noted that HRS cells showed many similarities to plasma cell malignancies such as multiple myeloma, notably their reliance on UPR signaling. However, unlike multiple myeloma, cHL cells fail to complete terminal plasma cell differentiation and do not consistently express CD138 or secrete immunoglobulins, showing that the two malignancies have only a partially shared differentiation trajectory.
The Weill Cornell team also found that immune evasion is another defining feature of cHL. They found evidence of downregulation of SLAM family ligands, including CD48, which are required for NK cell recognition and activation. This loss impairs NK cell-mediated cytotoxicity. The study also found reduced NK cell infiltration in tumor microenvironments. Additionally, HRS cells are known to evade T cell surveillance through antigen presentation defects and checkpoint ligand expression. Together, these findings show cHL mounts a coordinated escape from both innate and adaptive immunity.
The new findings could have implications for clinical care in the future. The identification of UPR dependency presents the opportunity to target proteostasis pathways as a treatment strategy.
“The UPR is a complex pathway, but there have been studies in solid tumors aiming to target it therapeutically, and in the context of multiple myeloma, it has been suggested that proteosomal inhibitors like bortezomib, act in part by leading to the accumulation of unfolded proteins leading to ER stress and eventually apoptosis,” Cesarman said. “While much more work needs to be done to fully characterize the UPR in Hodgkin lymphoma and identify therapeutically actionable aspects of this pathway, our findings point us in the right direction to explore the potential of such an approach.”
Cesarman also noted that while NK cell-based therapies are under development in oncology, the observed downregulation of NK ligands suggests this may not be a viable strategy for therapeutic development.
Future research will now focus on understanding more about how plasma cell differentiation programs become arrested in germinal center B cells, identifying upstream regulators of UPR activation in cHL, and determining whether these stress pathways are required for tumor cell survival. Additional studies are also expected to explore whether restoring immune recognition signals or targeting proteostasis can be combined with existing immune checkpoint therapies.
The post Hodgkin Lymphoma Develops as a Result of Arrested B Cell–Plasma Cell Transition appeared first on Inside Precision Medicine.