Now a research team, led by UCLA’s Anusha Kalbasi, MD, in collaboration with scientists from Stanford and the University of Pennsylvania, has shown that a synthetic IL-9 receptor allows those cancer-fighting T cells to do their work without the need for chemo or radiation. T cells engineered with the synthetic IL-9 receptor, designed in the laboratory of Christopher Garcia, PhD, at Stanford, were potent against tumors in mice, as published Wednesday in Nature.

“When T cells are signaling through the synthetic IL-9 receptor, they gain new functions that help them not only outcompete the existing immune system but also kill cancer cells more efficiently,” Kalbasi said. “I have a patient right now struggling through toxic chemotherapy just to wipe out his existing immune system so T cell therapy can have a fighting chance. But with this technology you might give T cell therapy without having to wipe out the immune system beforehand.”

Kalbasi, a researcher at the UCLA Jonsson Comprehensive Cancer Center and an assistant professor of radiation oncology at the David Geffen School of Medicine at UCLA, began the work while under the mentorship of Antoni Ribas, MD, PhD, a senior investigator on the study. The study was also led by Mikko Siurala, PhD, from the laboratory of Carl June, MD, at Penn, and Leon L. Su, PhD, of the Garcia Lab at Stanford.

“This finding opens a door for us to be able to give T cells a lot like we give a blood transfusion,” Ribas said.

Ribas and Garcia collaborated on a paper published in 2018 that focused on the concept that a synthetic version of interleukin-2 (IL-2), a critical T cell growth cytokine, could be used to stimulate T cells engineered with a matching synthetic receptor for the synthetic IL-2. With this system, T cells can be manipulated even after they have been given to a patient, by treating the patient with the synthetic cytokine (which has no effect on other cells in the body). Intrigued by that work, Kalbasi and colleagues were interested in testing modified versions of the synthetic receptor that transmit other cytokine signals from the common-gamma chain family: IL-4, -7, -9 and -21.

“It was clear early on that, among the synthetic common-gamma chain signals, the IL-9 signal was worth investigating,” Kalbasi said, adding that unlike other common-gamma chain cytokines, IL-9 signaling is not typically active in naturally occurring T cells. The synthetic IL-9 signal made T cells take on a unique mix of both stem-cell and killer-like qualities that made them more robust in fighting tumors. “In one of our cancer models, we cured over half the mice that were treated with the synthetic IL-9 receptor T cells.”

Kalbasi said the therapy proved to be effective in multiple systems. They targeted two types of hard-to-treat cancer models in mice — pancreatic cancer and melanoma — and used T cells targeted to cancer cells through the natural T cell receptor or a chimeric antigen receptor (CAR). “The therapy also worked whether we gave the cytokine to the whole mouse or directly to the tumor. In all cases, T cells engineered with synthetic IL-9 receptor signaling were superior and helped us cure some tumors in mice when we couldn’t do it otherwise.”

Setting out to investigate how social isolation and loneliness were related to later dementia, researchers at the University of Warwick, University of Cambridge and Fudan University used neuroimaging data from more than 30,000 participants in the UK Biobank data set. Socially isolated individuals were found to have lower gray matter volumes of brain regions involved in memory and learning.

The results of the study are published online today (June 8, 2022) in Neurology, the medical journal of the American Academy of Neurology, in a paper entitled “Associations of social isolation and loneliness with later dementia” by Shen, Rolls, Cheng, Kang, Dong, Xie, Zhao, Sahakian and Feng.

Based on data from the UK Biobank, an extremely large longitudinal cohort, the researchers used modelling techniques to investigate the relative associations of social isolation and loneliness with incident all-cause dementia. After adjusting for various risk factors (including socio-economic factors, chronic illness, lifestyle, depression and APOE genotype), socially isolated individuals were shown to have a 26% increased likelihood of developing dementia.

Loneliness was also associated with later dementia, but that association was not significant after adjusting for depression, which explained 75% of the relationship between loneliness and dementia. Therefore, relative to the subjective feeling of loneliness, objective social isolation is an independent risk factor for later dementia. Further subgroup analysis showed that the effect was prominent in those over 60 years old.

Professor Edmund Rolls, neuroscientist from the University of Warwick Department of Computer Science, said: “There is a difference between social isolation, which is an objective state of low social connections, and loneliness, which is subjectively perceived social isolation.

“Both have risks to health but, using the extensive multi-modal data set from the UK Biobank, and working in a multidisciplinary way linking computational sciences and neuroscience, we have been able to show that it is social isolation, rather than the feeling of loneliness, which is an independent risk factor for later dementia. This means it can be used as a predictor or biomarker for dementia in the UK.

“With the growing prevalence of social isolation and loneliness over the past decades, this has been a serious yet underappreciated public health problem. Now, in the shadow of the COVID-19 pandemic there are implications for social relationship interventions and care — particularly in the older population.”

Professor Jianfeng Feng, from the University of Warwick Department of Computer Science, said: “We highlight the importance of an environmental method of reducing risk of dementia in older adults through ensuring that they are not socially isolated. During any future pandemic lockdowns, it is important that individuals, especially older adults, do not experience social isolation.”

Professor Barbara J Sahakian, of the University of Cambridge Department of Psychiatry, said: “Now that we know the risk to brain health and dementia of social isolation, it is important that the government and communities take action to ensure that older individuals have communication and interactions with others on a regular basis.”

“Although optimism itself may be affected by social structural factors, such as race and ethnicity, our research suggests that the benefits of optimism may hold across diverse groups,” said Hayami Koga, a PhD candidate in the Department of Social and Behavioral Sciences at Harvard Chan School and lead author of the study. “A lot of previous work has focused on deficits or risk factors that increase the risks for diseases and premature death. Our findings suggest that there’s value to focusing on positive psychological factors, like optimism, as possible new ways of promoting longevity and healthy aging across diverse groups.”

The study will be published online on June 8, 2022, in the Journal of the American Geriatrics Society.

In a previous study, the research group determined that optimism was linked to a longer lifespan and exceptional longevity, which was defined as living beyond 85 years of age. Because they had looked at mostly white populations in that previous study, Koga and her colleagues broadened the participant pool in the current study to include women from across racial and ethnic groups. According to Koga, including diverse populations in research is important to public health because these groups have higher mortality rates than white populations, and there is limited research about them to help inform health policy decisions.

For this study, the researchers analyzed data and survey responses from 159,255 participants in the Women’s Health Initiative, which included postmenopausal women in the U.S. The women enrolled at ages 50-79 from 1993 to 1998 and were followed for up to 26 years.

Of the participants, the 25% who were the most optimistic were likely to have a 5.4% longer lifespan and a 10% greater likelihood of living beyond 90 years than the 25% who were the least optimistic. The researchers also found no interaction between optimism and any categories of race and ethnicity, and these trends held true after taking into account demographics, chronic conditions, and depression. Lifestyle factors, such as regular exercise and healthy eating, accounted for less than a quarter of the optimism-lifespan association, indicating that other factors may be at play.

Koga said that the study’s results could reframe how people view the decisions that affect their health.

“We tend to focus on the negative risk factors that affect our health,” said Koga. “It is also important to think about the positive resources such as optimism that may be beneficial to our health, especially if we see that these benefits are seen across racial and ethnic groups.”

This research was supported by the National Institutes of Health (R01AG053273, K08048221). The Women’s Health Initiative is funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health, and the Department of Health and Human Services.

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Materials provided by Harvard T.H. Chan School of Public Health. Note: Content may be edited for style and length.