TIM-3 Blockade in Dendritic Cells Potentiates Anti-Tumor Immunity

A recent study on T cell immunoglobulin and mucin-containing molecule 3 (TIM-3) from the lab of Vijay Kuchroo, DVM, PhD, at the Brigham’s Evergrande Center for Immunologic Diseases has uncovered a new role for TIM-3 on dendritic cells (DCs). The research team found that TIM-3 expression in dendritic cells inhibits anti-tumor immunity by regulating the inflammasome. Insights into TIM-3 function in myeloid cells can guide future use of TIM-3 blockade to enhance anti-tumor immunity. TIM-3 is implicated as an immune checkpoint molecule and is expressed on several different types of immune cells. However, exactly how therapeutic blockade of TIM-3 might influence anti-tumor immunity is currently unknown. Investigators generated conditional knock-out mice to specifically delete TIM-3 in T cells, but found little effect. Surprisingly, targeted deletion of TIM-3 in DCs resulted in a reduction in tumor burden in mice engrafted with colon, lung, or melanoma cells. TIM-3 deletion in DCs resulted in accumulation of reactive oxygen species, activating the NLRP3 inflammasome. Blocking inflammasome activation either directly or via inhibition of downstream effector cytokines IL-1β and IL-18 reversed the anti-tumor effects of deletion of TIM-3.

“Our findings reveal an important role for TIM-3 in regulating DC function and underscore the potential of TIM-3 blockade in promoting anti-tumor immunity by regulating inflammasome activation,” said Karen Dixon, PhD, from the Brigham’s Evergrande Center for Immunologic Diseases and the Ann Romney Center for Neurologic Diseases. “These results build on growing interest in new pathways to target in cancer and underscore the value of TIM-3 blockade on myeloid cells as a potential target for cancer treatment.”

Read more in Nature.

All of Us Cohort Found to Have Similar Rates of Hypertension Compared to Prior Surveys

A new study from the All of Us Research Program examines the prevalence of hypertension (HTN) among groups traditionally underrepresented in medical research compared to data from the 2015-2016 National Health and Nutrition Examination Survey (NHANES). The study used retrospective data from patient measurements, surveys and electronic health records (EHR) blood pressure measurements. HTN was defined as having at least two HTN diagnosis on separate dates and at least one HTN medication. Of the 185,770 participants enrolled in AoU, prevalence of HTN was 27.9 percent. In NHANES, HTN prevalence was 29.6 percent. Similarly, the known associations between race, socioeconomic status, and geographic region and hypertension prevalence were reproduced in AoU. The researchers concluded that, in their efforts to better HTN treatment and prevention, the prevalence is similar to other population-based surveys.

“We have shown that AoU data yields similar prevalence estimates, which supports the data’s validity.” said Paulette Denise Chandler, MD, MPH, an internal medicine doctor at the Brigham. “The diversity within AoU may provide insight into factors relevant to HTN prevention and treatments in a variety of social and geographic contexts and population strata in the U.S. given that over 80 percent of AoU participants have been historically underrepresented in biomedical research from the perspectives of age, race/ethnicity, sexual orientation and gender identity, geography or other dimensions.”

Read more in Scientific Reports.

New Investigation Finds Unstudied Benefits of Docetaxel in Men with Aggressive Prostate Cancer

Although the chemotherapy drug docetaxel is not recommended for men with unfavorable-risk prostate cancer, a new Brigham study suggests that there are clinically important benefits to this agent. Between September 2005 and January 2015, 350 men with unfavorable-risk prostate cancer were randomly assigned to receive either radiation therapy (RT), androgen deprivation therapy (ADT) and docetaxel, or RT and ADT only. The median follow-up period was 10.2 years, after which 25 percent of patients had died. Of the deceased patients, 47 percent died of prostate cancer. The research team concluded that while adding docetaxel to the ADT and RT treatment plan did not prolong overall survival among all men with unfavorable risk prostate cancer, it did decrease RT-induced cancer and appeared to prolong overall survival in men with very aggressive prostate cancer by reducing prostate cancer-specific mortality.

“These data enable identification of a subgroup of men with aggressive high-grade prostate cancer based on a PSA level < 4 ng/mL who appear to benefit from docetaxel,” said Anthony D’Amico, MD, PhD, professor and chief of Genitourinary Radiation Oncology at Brigham and Women’s Hospital and Dana-Farber Cancer Institute. “Our data also show that docetaxel significantly reduced and possibly eliminated radiation induced cancers which are often lethal.”

Read more on this research in the Journal of Clinical Oncology.

A Framework for the Future of Molecular Cancer Screening

New molecular technologies for cancer screening — such as germline genetic sequencing and liquid biopsy — could help detect cancer early and reduce the burden of cancer death. But important questions remain about how much evidence is needed to validate these tests before they are implemented in the clinic. High false-positive rates could lead to exorbitant health care costs, and regulatory agencies must weigh such costs against clinical utility. A commentary written by co-authors who include researchers from Massachusetts General Hospital and The Precision Population Health (PPH) initiative, a collaboration between the Brigham’s Genomes2People and Ariadne Labs, seeks to chart a middle ground for evaluating innovative screening technologies

“The importance of the article is that it takes on the challenge of how regulatory agencies should handle the roll out of fast moving innovative molecular technologies where the product is going to market long before there is definitive evidence that it is medically justified,” said senior author Robert Green, MD, MPH, director of Genomes2People and a medical geneticist at the Brigham. “Regardless of whether the medical community is ready, new molecular screening technologies are being invented, refined, clinically studied and commercially promoted. No matter how difficult, it is essential that an appropriate path is found toward implementation, while the guardrails of evidence-based medicine and sound health-economic decision-making are maintained.”

Read more in Nature Medicine.

Study Uncovers a Rejuvenation Event During Embryogenesis Followed by Aging

A new study from the Brigham’s Gladyshev Lab has found that there is a significant decrease in biological age during the early stages of embryogenesis. Vadim Gladyshev, PhD, a professor of Medicine at the Brigham and Harvard Medical School and the leader of the research group, recently proposed that germline cells may age and be rejuvenated in offspring after conception. Consequently, there must be a point of the lowest biological age, which the researchers refer to as ground zero, during early embryogenesis. To test this idea, they evaluated both human and mouse DNA methylation data with various epigenetic clocks to assess the biological age (i.e. age based on molecular markers) during embryogenesis.

“Our study suggests that the germ line ages but is rejuvenated in the offspring at some point during early embryogenesis, approximately at the time of gastrulation,” said Gladyshev. “We propose that this minimum, the ground zero, marks the beginning of aging of an organism.”

“Aging is frequently thought to begin in adulthood. However, when we applied epigenetic aging clocks (molecular measures of biological age) to different tissues of mice and humans, the data surprisingly showed that aging begins in embryonic development in mice and prenatally in humans,” said lead author Csaba Kerepesi, PhD, a Hungarian-born research fellow at the Brigham. “This result is consistent with a previous analysis of age-related deleterious changes done in our lab that suggested that aging begins somewhere in early life.”

Read more in Science Advances.

Among Older Adults, Disruptions in Daily Behaviors Predicted Depression, Anxiety About the Pandemic

Over the past year and a half, people everywhere have experienced mental health repercussions as a result of the COVID-19 pandemic. With older adults having increased risk of serious illness due to the virus, senior populations were advised to shelter-in-place and avoid gatherings. A research team from the Brigham tracked the relationship between disruptions in daily behaviors such as changes in sleep patterns, consumption of alcohol and exercise among older adults. The team found that these changes were the strongest predictors of depression and anxiety related to the pandemic. From their analysis of 3,122 older adults in the US, the researchers found that worse sleep quality, sleeping more or less, watching more television and walking less were all associated with increased feelings of depression and anxiety about the COVID-19 pandemic.

“While previous research has examined the drastic changes to daily life associated with the COVID-19 pandemic, such as avoiding socializing with others and spending long periods of time sheltering in place, less attention has been devoted to the changes to our daily health behaviors, such as exercise, nutrition, and sleep, and their implications for emotional well-being,” said Rebecca Robbins, PhD, of the Brigham’s Division of Sleep and Circadian Disorders. “We found that of all changes to our daily routines, those pertaining to our sleep duration and sleep quality were among the strongest predictors of adverse emotional impacts of the pandemic among older adults.”

Read more in the Journal of Gerontology Social Sciences.

Restoring PTEN with Help from Synthetic mRNA Nanoparticles to Improve Immunotherapy

One of cancer’s signature moves is to disable the gene encoding phosphatase and tensin homolog deleted on chromosome ten (PTEN). PTEN is a key tumor suppressor and its loss makes tumor cells far more difficult to treat with immunotherapy. Investigators from the Brigham are working on a new way to restore PTEN using synthetic mRNA nanoparticles that can deliver functional PTEN and elicit anti-tumor immune responses in PTEN-null or mutated tumor models. In preclinical models, the team found that PTEN reactivation sensitized PTEN-null or mutated tumors to immune checkpoint immunotherapy.

“This strategy may represent a new type of tumor suppressor-specific precision immunotherapy for cancer treatment,” said corresponding author Jinjun Shi, PhD, of the Department of Anesthesiology, Perioperative and Pain Medicine. “In this work, we revealed that PTEN reactivation can further induce anti-tumor immune responses and improve immunotherapy in immunocompetent tumor models.”

Results are published in Science Translational Medicine.

Researchers Find Only Modest Intensification of Lipid Lowering Therapies Among Patients with Heart Disease

A new investigation from the Brigham’s Division of Cardiovascular Medicine describes and tracks the use of lipid-lowering therapies (LLT) for patients with atherosclerotic cardiovascular disease (ASCVD). The Getting to an Improved Understanding of Low-Density Lipoprotein-Cholesterol and Dyslipidemia Management (GOULD) registry is a multicenter, observational registry of patients with ASCVD.  Any patients with ASCVD already receiving LLT were eligible for the study if they were receiving a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) or had LDL-C levels >70 mg/dL. Medical record reviews and phone interviews took place every six months for two years to track progress. Over that period, only 1 in 3 patients achieved an LDL-cholesterol level less than 70 mg/dL and only modest intensification of LLT was observed.

“We found in patients with known heart disease and an LDL above guideline recommended levels, only 17% had in intensification of their therapy – over a two year period,” said corresponding author Christopher Cannon, MD, from the Brigham’s Division of Cardiovascular Medicine. “There was a 2-4 percent annual increase in use of more intensive agents, despite the results of large cardiovascular outcomes trials and updates to national guidelines in 2018. We need to work with our patients and get the bad cholesterol levels down.”

Read more in JAMA Cardiology.