The field of immunotherapy – the harnessing of patients’ own immune systems to fend off cancer – is revolutionizing cancer treatment today. However, clinical trials often show marked improvements in only small subsets of patients, suggesting that as-yet unidentified variations among tumours result in distinct paths of disease progression and response to therapy.
Now, researchers at the Cancer Center at Beth Israel Deaconess Medical Center (BIDMC) have demonstrated that genetic variations driving prostate cancer determine the composition of the immune cells that have been found to infiltrate primary prostate tumours. These immune cells, in turn, dictate tumour progression and response to treatment. The data suggest that profiling patients’ tumours based on this new information could lead to more successful clinical trials and tailored therapies for patients.
“We observed that specific genetic events resulted in striking differences in the composition of immune cells present in and around the tumour – results with important therapeutic implications,” said senior author Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Center and Cancer Research Institute at BIDMC. “Our data may be especially relevant for tailoring immunological therapies and for identifying responsive-patient population.”
The third leading cause of cancer-related death in U.S. men, prostate cancer, is linked to a number of diverse genetic mutations that drive the disease. For example, the loss of the tumour suppressor gene PTEN is a frequent event in prostate cancer and is well known to promote the disease in combinations with a plethora of other mutations. Researchers also know that the tumour’s microenvironment – the blood vessels, immune cells, signalling molecules and other factors that surround the tumour – plays an important role in tumour progression and response to therapy.
Pandolfi’s team – including lead author, Marco Bezzi, a post-doctoral fellow in Pandolfi’s lab – engineered mice models to represent four distinct known genetic variations of human prostate cancer. The models lacked either Pten alone or in combination with other genetic alterations known to drive the disease. When the team analysed the tumours from these mice, they saw profound differences in the types and relative numbers of the immune cells that had accumulated in and around the tumour, what they call the tumours’ “immune landscape”.
For example, specific immune landscapes tumours from the genetic model lacking both Pten and the tumour suppressor gene called Trp53 demonstrated an increased accumulation of myeloid cells, the immune cells that mediate immunosuppression. In stark contrast, tumours from the genetic model lacking Pten and a different tumour suppressor gene called PML lacked intratumoral immune infiltration; that is, the researchers observed no immune cells at all in these tumours, which the scientists dubbed “cold,” or “immune-deserts.” All four mouse models analysed presented very distinctive immune landscapes and these differences were maintained and exacerbated over time.
The research team also demonstrated that these differences in immune cell composition were directly dictated by the tumours themselves because of their genetic variations. Different tumours, they observed, secreted distinct chemical attractants, which in turn recruited – or didn’t recruit, in the case of the immune-desert tumours – different immune cell types into the tumour. Pandolfi and colleagues further demonstrated that these differences hold true in human prostate cancer. Critically, the immune cells recruited to the tumours were found to be essential in supporting the growth and progression of these tumours.
“We observed that when present, these infiltrating immune cells were required for the tumour to thrive and found therapies to block their recruitment to be effective,” said Bezzi. “On the other hand, the cancer genotype characterized by the so-called ‘immune desert’ phenotype, did not respond to such therapies. On this basis, we can predict the tumour response to immunotherapies and tailor treatment modalities to effectively impact tumors that are otherwise extremely aggressive,” he said. 
Thus, because immune cells interact with and also affect tumour response to therapy, these findings may be especially relevant for the development of more precise and effective combinations of immunotherapies and targeted therapies on the basis of the cancer genetic makeup.
Beth Israel Deaconess Medical Centerwww.bidmc.org/News/PRLandingPage/2018/January/Pandolfi-Bezzi.aspx

Researchers have identified a type of human leukocyte antigen (HLA) that is associated with the skin disease bullous pemphigoid (BP) in diabetic patients administered with DPP-4 inhibitory drugs.
DPP-4 inhibitor (DPP-4i) is widely used to treat type 2 diabetes, but increased cases of bullous pemphigoid (BP) have been reported among patients taking the medicine. BP is the most common autoimmune blistering disorder, characterized by itchy reddening of the skin as well as tense blisters over the whole body. Afflicted patients, mostly elderly, suffer from autoimmune attacks on a type of collagen in skin, making it hard to cure and compromising their quality of life. Previously, no risk factor triggering BP in diabetic patients administered with DPP-4i had been identified.
BP is classified into two types: inflammatory and non-inflammatory, the latter of which is found more in diabetic patients administered with the drug. The research team, including Dr. Hideyuki Ujiie of Hokkaido University Hospital, examined 30 BP patients administered with DPP-4i, and investigated their symptoms and autoantibodies to group them as inflammatory or noninflammatory.
The researchers then analysed human leukocyte antigen (HLA) genes of the 30 patients to identify their white blood cell type since HLA genes are known to be involved in various immune diseases. To compare, the team also analysed the HLA of 72 BP patients who had not been administered with DPP-4i and 61 diabetic patients who were using the drug but not affected by BP. Their findings were compared with the HLA genes of 873 Japanese from the general population.
According to the results, 70 percent of the 30 BP patients administered with DPP-4i fell into the non-inflammatory type with less reddening of the skin (erythema). HLA analyses found 86 percent of the non-inflammatory BP patients administered with DPP-4i had an HLA gene called “HLA-DQB1*03:01.” The rate of having the HLA gene was much higher than was detected among the general population (18 percent) and non-BP type-2 diabetic patients administered with DPP-4i (31 percent). Meanwhile, 26 percent of BP patients who were not administered with the drug had the same HLA gene.
The findings show HLA-DQB1*03:01 is not linked to ordinary BP nor type-2 diabetes, but is closely associated with the development of BP among DPP-4i takers. “However, as the probability of patients exposed to DPP-4i to develop BP remains unclear, further research investigating a much larger number of cases is needed,” says Hideyuki Ujiie.
“Our results suggest people with HLA-DQB1*03:01 have a higher risk of developing BP when exposed to DPP-4i than those without the HLA gene. The gene could serve as a biomarker to help estimate the risk of developing BP when patients are administered with DPP-4i. The mechanism that connects the HLA gene and BP needs to be addressed to help prevent the development of the disease,” Ujiie added.
ScienceDailyhttps://tinyurl.com/y9u48zv3 

A group of investigators from Mayo Clinic and multiple academic research centres in Italy have identified a genetic model for predicting outcomes in patients with primary myelofibrosis who are 70 years or younger and candidates for stem cell transplant to treat their disease.
“Myelofibrosis is a rare type of chronic leukemia that disrupts the body’s normal production of blood cells,” says Dr. Tefferi. “Prior to this study, the most comprehensive predictive model for outcomes in myelofibrosis, utilized mostly clinical variables, such as age, hemoglobin level, symptoms, white blood cell count and the percentage of immature cells in the peripheral blood.”
Dr. Tefferi says he and his colleagues incorporated new genetic tests in the model for gene mutations including JAK2, CALR, and MPL, which are known to drive myelofibrosis. He says the new model also tests for the presence or absence of high-risk mutations such as ASXL1 and SRSF2. “Our model is also unique in that we developed it for patients who are age 70 years or younger who may still be candidates for a stem cell transplant to treat their disease,” Dr. Tefferi says.
Researchers studied 805 patients with primary myelofibrosis who were 70 years of age or younger. Patients were recruited from multiple centres in Italy and from Mayo Clinic in Minnesota. The Italian and Minnesota groups formed two independent learning and validation cohorts. “We were surprised by how similar the predictive models performed in two completely separate patient databases,” Dr. Tefferi says.
Dr. Tefferi says that genetic information is increasingly being used as a prognostic biomarker in patients with primary myelofibrosis and he anticipates the potential use of such an approach along with relevant clinical, cytogenetic and mutational data for other hematologic and non-hematologic cancers.
Mayo Clinic Cancer Centerhttps://tinyurl.com/y7zlxtqz

Clearing a major hurdle in the field of microbiome research, Harvard Medical School scientists have designed and successfully used a method to tease out cause-and-effect relationships between gut bacteria and disease.
The team says the approach could propel research beyond mere microbiome-disease associations and elucidate true cause-effect relationships.
The experiments, conducted in mice, also identify a previously unknown gut microbe that tames intestinal inflammation and protects against severe colitis. The researchers say the finding makes a strong case for testing the newly identified gut bacterium as a probiotic therapy in people with inflammatory bowel disease, a constellation of conditions marked by chronic inflammation of the intestines and estimated to affect up to 1.3 million people in the United States, according to the Centers for Disease Control and Prevention.
The approach uses a sort of “microbial triangulation.” It mimics the principles of classic maritime navigation or, in more modern terms, tracking the location of a mobile phone by verifying data from multiple sources—but instead of stars or cell phone towers, the researchers are homing in on intestinal bugs. Based on the method of elimination, the technique involves the gradual narrowing down of bacterial species to identify specific microbes that modulate the risk for specific diseases. In the current study, researchers adapted the principles to identify beneficial, protective bacteria.
“Our approach can help scientists find the proverbial needles in a ‘haystack’ of thousands of microbes that are currently thought to modulate health,” said investigator Dennis Kasper, professor of microbiology and immunobiology at Harvard Medical School. “If the field is to move past associations—the Achilles’ heel in microbiome research—we need a system that reliably teases out causative relationships between gut bacteria and disease. We believe our method achieves that,” added Kasper, who is also the Harvard Medical School William Ellery Channing Professor of Medicine at Brigham and Women’s Hospital.
Over the last decade, study after study has identified thousands of commensal microbes—those residing innocently in our bodies—and catalogued observations of possible links between groups of microbes and the presence or absence of a panoply of diseases, including diabetes, multiple sclerosis and inflammatory bowel disease. Yet, scientists don’t know whether and how the presence of specific microbes—or fluctuations in their numbers—affects health. It remains unclear whether certain microbes are innocent bystanders, mere markers of disease, or whether they are active agents, causing harm or providing protection against certain ailments.
The holy grail of this work would be not to merely define whether a microbe fuels or minimizes the risk for a given disease but to discover microbes and microbial molecules that can be used therapeutically.
“The ultimate goal is to clarify the mechanisms of disease and then identify bacterial molecules that can be used to treat, reverse or prevent it,” said study lead author Neeraj Surana, Harvard Medical School instructor in pediatrics and an infectious disease specialist at Boston Children’s Hospital.
For their study, Kasper and Surana compared the gut microbiomes of several groups of mice that harboured different populations of intestinal bacteria.
The researchers started out with two groups of mice. One group had been bred with human gut microbiomes—housing intestinal bacteria normally found in human intestines. The other group had been bred to harbour normal mouse microbiomes. When researchers gave the animals a chemical compound that triggered intestinal inflammation, or colitis, mice that harboured human intestinal microbes were protected from the effects of the disease. Mice whose guts harboured typical mouse bacteria, however, developed severe symptoms.
Next, the researchers housed all mice in the same living space. Sharing living space for as briefly as one day led to noticeable changes in how the animals responded to disease. Mice that had been originally protected from colitis started showing more serious signs of it, while colitis-prone mice grew increasingly resistant to the effects of the condition and developed milder symptoms—a proof-of-principle finding which shows that exchange of intestinal bacteria through shared living space can lead to changes in the animals’ ability to cope with the disease.
The disease-modulating microbe would be lurking amid the hundreds of bacterial species present in all mice. But given that each mouse group harboured between 700 and 1,100 bacterial species in their guts, how could scientists identify the one that truly mattered in colitis? The team began by analysing the intestinal makeup of each one of the mouse groups, comparing their microbial profiles before and after they shared a living space. To “triangulate” the suspect’s identity, scientists looked for microbes that were either scarce or abundant, tracking with colitis severity. In other words, the numbers of the causative microbe would either go up or down with disease severity, the scientists reasoned. Only one such microbial group fit the profile—a bacterial family known as Lachnospiraceae, commonly found in human intestines as well as the guts of other mammals.
To pinpoint the one organism within the Lachnospiraceae family that regulates response to colitis, the researchers isolated one bacterial species and gave it to colitis-prone mice. To compare its effects against other microbes, they also gave the animals organisms from different bacterial families. The only bacterium that protected colitis-prone animals from the ravages of the disease was a never-before-described microbe that the researchers had isolated from the guts of mice seeded with human feces, the animals that had harboured human microbiomes. The microbe was notably absent from mice with mouse microbiomes. Because of its immune-protective properties, Kasper and Surana christened the newly identified organism Clostridium immunis.
The isolation of the disease-modifying microbe makes a powerful case for testing it as therapy in people with inflammatory bowel disease, the researchers said.
Harvard Medical Schoolhttps://tinyurl.com/yawe5qvh

A gene which could play a role in causing the most severe cases of club foot has been identified by scientists at the University of Aberdeen.
Clubfoot is a lower leg abnormality, where babies are born with the foot in a twisted position, facing inwards and upwards rather than flat to the floor.  It is quite common, affecting about 1 baby in every 1,000 born in the UK.  Of those, 1,000 about half have the condition in both feet.
The causes of clubfoot are very poorly understood, though it sometimes runs in families and it is known that genes are involved.
Experts believe the condition is a neuro-muscular problem – a result of muscle weakness in the legs during development. However it is difficult to pinpoint the causes because there are so many different things that can cause muscle weakness.
The condition requires lengthy treatment involving manipulation, putting the feet in a cast (called the Ponseti method) an operation and then a requirement to wear specialised boots joined together by a metal bar at night until the age of four or five years old.
In severe cases, which are often associated with failure of the nerves to calf muscles, even after this treatment the foot can bend back, meaning a more invasive surgery is required.
The Aberdeen team believe they may have identified a gene in a mouse model which is linked to the more serious cases of clubfoot in humans.
The gene (Limk1) is required for normal nerve growth and has shown to be part of a pathway of genes, one of which is already known to be linked to clubfoot in mice.
Professor Martin Collinson, a geneticist from the University of Aberdeen, and leader of the study says: “This is, hopefully, another piece in the puzzle of what causes clubfoot in humans. Our hypothesis is that probably for most human clubfoot patients, it’s not just one gene that goes wrong, there are probably predisposed mutations in several genes in these pathways and they add up to eventually cause muscle weakness.
“The next stage is to look at DNA samples taken from human clubfoot patients and screen them to see if there are mutations in these pathways.
“Club foot is commonly treated successfully using the Ponseti method but it may be that the feet of children with these gene deformations will just revert back once treatment is finished. In theory if we could screen children for these genes before treatment starts, then they could avoid years of unnecessary interventions.”
University of Aberdeenwww.abdn.ac.uk/news/11665/