An urgent question for cancer scientists is why immunotherapy achieves dramatic results in some cases but doesn’t help most patients. Now, two research groups from Dana-Farber Cancer Institute have independently discovered a genetic mechanism in cancer cells that influences whether they resist or respond to immunotherapy drugs known as checkpoint inhibitors.
The scientists say the findings reveal potential new drug targets and might aid efforts to extend the benefits of immunotherapy treatment to more patients and additional types of cancer.
One report, focusing on clinical trial patients with advanced kidney cancer treated with checkpoint inhibitors, is from scientists at Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard, led by Eliezer Van Allen, MD, of Dana-Farber and the Broad, and Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber.
The second report, which identifies the immunotherapy resistance mechanism in melanoma cells, is from a group led by Kai Wucherpfennig, MD, PhD, director of Dana-Farber’s Center for Cancer Immunotherapy Research, and Shirley Liu, PhD, of Dana-Farber.
The two groups converged on a discovery that resistance to immune checkpoint blockade is critically controlled by changes in a group of proteins that regulate how DNA is packaged in cells. The collection of proteins, called a chromatin remodelling complex, is known as SWI/SNF; its components are encoded by different genes, among them ARID2, PBRM1, and BRD7. SWI/SNF’s job is to open up stretches of tightly wound DNA so that its blueprints can be read by the cell to activate certain genes to make proteins.
Researchers led by Van Allen and Choueiri sought an explanation for why some patients with a form of metastatic kidney cancer called clear cell renal cell cancer (ccRCC) gain clinical benefit — sometimes durable — from treatment with immune checkpoint inhibitors that block the PD-1 checkpoint, while other patients don’t.
The scientists’ curiosity was piqued by the fact that ccRCC differs from other types of cancer that respond well to immunotherapy, such as melanoma, non-small cell lung cancer, and a specific type of colorectal cancer. Cells of the latter cancer types contain many DNA mutations, which are thought to make distinctive "neoantigens" that help the patient’s immune system recognize and attack tumours, and make the cancer cells’ “microenvironment” hospitable to tumour-fighting T cells. By contrast, ccRCC kidney cancer cells contain few mutations, yet some patients even with advanced, metastatic disease respond well to immunotherapy.
To search for other characteristics of ccRCC tumours that influence immunotherapy response or resistance, the researchers used whole-exome DNA sequencing to analyse tumour samples from 35 patients treated in a clinical trial with the checkpoint blocker nivolumab (Opdivo). They also analysed samples from another group of 63 patients with metastatic ccRCC treated with similar drugs.
When the data was sorted and refined, the scientists discovered that patients who benefited from the immunotherapy treatment with longer survival and progression-free survival were those whose tumours lacked a functioning PRBM1 gene. (About 41 percent of patients with ccRCC kidney cancer have a non-functioning PRBM1 gene.) That gene encodes a protein called BAF 180, which is a subunit of the PBAF subtype of the SWI/SNF chromatin remodelling complex.
Loss of the PRBM1 gene function caused the cancer cells to have increased expression of other genes, including a gene pathway known as IL6/JAK-STAT3, which are involved in immune system stimulation.
While the finding does not directly lead to a test for immunotherapy response yet, Choueiri said, "We intend to look at these specific genomic alterations in larger, randomized controlled trials, and we hope that one day these findings will be the impetus for prospective clinical trials based on these alterations."
In the second report, the scientists led by Wucherpfennig came at the issue from a different angle. They used the gene-editing CRISPR/Cas9 technique to sift the genomes of melanoma cells for changes that made tumours resistant to being killed by immune T cells, which are the main actors in the immune system response against infections and cancer cells.
The search turned up about 100 genes which appeared to govern melanoma cells’ resistance to being killed by T cells. Inactivating those genes rendered the cancer cells sensitive to T-cell killing. Narrowing down their search, the Wucherpfennig team identified the PBAF subtype of the SWI/SNF chromatin remodelling complex — the same group of proteins implicated by the Van Allen and Choueiri team in kidney cancer cells — as being involved in resistance to immune T cells.
When the PRBM1 gene was knocked out in experiments, the melanoma cells became more sensitive to interferon-gamma produced by T cells, and in response produced signaling molecules that recruited more tumor-fighting T cells into the tumor. The two other genes in the PBAF complex — ARID2 and BRD7 — are also found mutated in some cancers, according to the researchers, and those cancers, like the melanoma lacking ARID2 function, may also respond better to checkpoint blockade. The protein products of these genes, the authors note, "represent targets for immunotherapy, because inactivating mutations sensitize tumor cells to T-cell mediated attack." Finding ways to alter those target molecules, they add, "will be important to extend the benefit of immunotherapy to larger patient populations, including cancers that thus far are refractory to immunotherapy."
Dana-Farber Cancer Institutewww.dana-farber.org/newsroom/news-releases/2018/mechanism-for-resistance-to-immunotherapy-treatment-discovered/

The research carried out at Queen Mary University of London, University of Exeter and Vanderbilt University could lead to the development of novel treatments for both rare and common forms of diabetes.
In addition to the more common forms of diabetes (type 1 or type 2), in about 1-2 per cent of cases diabetes is due to a genetic disorder, known as maturity onset diabetes of the young (MODY). A defective gene typically affects the function of insulin-producing cells in the pancreas, known as beta cells.
The research team studied the unique case of a family where several individuals suffer from diabetes, while other family members had developed insulin-producing tumours in their pancreas. These tumours, known as insulinomas, typically cause low blood sugar levels, in contrast to diabetes which leads to high blood sugar levels.
Lead author Professor Márta Korbonits from Queen Mary’s William Harvey Research Institute said: “We were initially surprised about the association of two apparently contrasting conditions within the same families – diabetes which is associated with high blood sugar and insulinomas associated with low blood sugar. Our research shows that, surprisingly, the same gene defect can impact the insulin-producing beta cells of the pancreas to lead to these two opposing medical conditions.”
The team also observed that males were more prone to developing diabetes, while insulinomas were more commonly found in females, but the reasons behind this difference are as yet unknown.
Professor Korbonits added: “One exciting avenue to explore will be seeing if we can use this finding to uncover new ways to help regenerate beta cells and treat the more common forms of diabetes.”
The researchers identified a genetic disorder in a gene called MAFA, which controls the production of insulin in beta cells. Unexpectedly, this gene defect was present in both the family members with diabetes and those with insulinomas, and was also identified in a second, unrelated family with the same unusual dual picture.
This is the first time a defect in this gene has been linked with a disease. The resultant mutant protein was found to be abnormally stable, having a longer life in the cell, and therefore significantly more abundant in the beta cells than its normal version.
First author Dr Donato Iacovazzo from Queen Mary’s William Harvey Research Institute added: “We believe this gene defect is critical in the development of the disease and we are now performing further studies to determine how this defect can, on the one hand, impair the production of insulin to cause diabetes, and on the other, cause insulinomas.”
Queen Mary University of Londonwww.qmul.ac.uk/media/news/2018/smd/diabetes-gene-found-that-causes-low-and-high-blood-sugar-levels-in-the-same-family.html

Germline mutations in certain genes are known to cause inherited cancer. Thus, individuals carrying mutations in the so-called breast cancer type I and II genes (BRCA1 and BRCA2) are highly prone to breast as well as ovarian cancers. In cancers, both gene mutations and aberrant regulation of genes (promoter inhibition by methylation of DNA) are known to play pivotal roles regulating cancer growth.
An issue of controversy has been whether aberrant promoter methylation in normal tissue may be a cancer risk factor. Researchers from Haukeland University Hospital in Bergen, Norway, and colleagues analysed for potential impact of normal tissue BRCA1 methylation on ovarian cancer risk. Analysing white blood cells from 934 patients and 1,698 healthy controls, they found BRCA1 methylation among 6.4% of patients diagnosed with ovarian cancer, contrasting 4.2% among controls. Importantly, elevated BRCA1 methylation was confined to patients diagnosed with so-called high-grade serous tumours, the most aggressive variant of ovarian cancer, which also is the variant associated with BRCA1 mutations. Among patients with high-grade serous cancers, methylation was detected among 9.6% of individuals, corresponding to an almost 3-fold increase in risk for individuals harbouring methylation (age-adjusted odds ratio of 2.91). As for non-serous or low-grade serous cancers, methylation frequency resembled controls (5.1% and 4.0%, respectively). In the same report, the researchers replicated these findings in an independent validation study in which they found methylation among 9.1% of patients with high-grade serous cancers versus 4.3% among controls.
According to the authors, it is important to note that white blood cell BRCA1 methylation was detected also among newborns and young adults, indicating that normal tissue BRCA1 methylation may occur as a prenatal event. These findings have significant implications to the understanding of normal tissue methylation and strongly indicate that events occurring before birth influence cancer risk later in life.
bioengineer.orgbioengineer.org/normal-tissue-brca1-methylation-associated-with-risk-for-high-grade-ovarian-cancer/

The failure of drugs such as SSRIs, used to treat depression, can be a result of genetic variations in patients. Variations within the gene that encodes the CYP2C19 enzyme results in extreme differences in the levels of escitalopram achieved in patients. Prescribing the dose of escitalopram based on a patient’s specific genetic constitution would greatly improve therapeutic outcomes. The study was conducted at Karolinska Institutet in association with researchers at Diakonhjemmet Hospital in Oslo.
Pharmaceutical treatment of depression commonly makes use of selective serotonin reuptake inhibitors (SSRIs) of which escitalopram is the most frequently administered clinically. However, escitalopram therapy is currently limited by the fact that some patients do not respond well to the drug, while others develop adverse reactions requiring discontinuation of treatment.
In order to individualise drug therapy, researchers are attempting to establish genetic biomarkers that can predict an individual’s response to drugs. In a recent study, it was discovered that variation in the gene encoding the enzyme responsible for escitalopram metabolism (CYP2C19) is very important in this respect. Individuals with a variant of the gene promoting increased enzyme expression had blood levels of escitalopram too low to impact the depression symptoms, whereas patients with a defective CYP2C19 gene reached drug levels which were too high. Overall, one third of the 2,087 study participants achieved escitalopram blood levels that were either too high or too low.
Interestingly, the researchers found that 30 per cent of the patients carrying gene variants causing excessive or inadequate enzyme levels switched to other drugs within one year, in contrast with only 10 to 12 per cent of patients carrying the common gene.
“Our study shows that genotyping of CYP2C19 could be of considerable clinical value in individualising doses of escitalopram so that a better all-round antidepressive effect could be achieved for the patients,” says Professor Magnus Ingelman-Sundberg at Karolinska Institutet’s Department of Physiology and Pharmacology who led the study together with Professor Espen Molden. “Because CYP2C19 is involved in the metabolism of many different SSRIs, the finding is also applicable to other types of antidepressants.”
Karolinska Instituteki.se/en/news/genetic-analysis-can-improve-depression-therapy

The retinoblastoma (RB) susceptibility gene was the first gatekeeper gene discovered for cancer. When it was removed or damaged, cancer thrived. Over the years, researchers have discovered methods that have allowed them to experimentally remove the RB gene in order to study it, but just how the gene’s loss made cancers more aggressive was poorly understood. By studying patient samples, researchers at the Sidney Kimmel Cancer Center at Jefferson (SKCC) found how one type of RB removal, but not another, caused large-scale genetic changes that could make cancer both resistant to treatment and more likely to spread.
“RB loss causes a major reprogramming of gene expression, allowing induction of pathways that promote features that induce characteristics of lethal disease,” said senior author Karen Knudsen, PhD, Director of the SKCC. The study is the first to identify the molecular consequences of RB loss and illustrate the clinical relevance of RB loss-induced transcriptional rewiring.
The study involved a multinational collaboration between SKCC investigators and other US-based laboratories, as well as clinical and basic science researchers in the UK, Italy, Belgium, Finland and Sweden.
The study, which was spearheaded by first author Christopher McNair, PhD, a graduate student in the laboratory of Dr. Knudsen, undertook an extensive analysis of tumour samples and cell-free DNA samples from patients with advanced, lethal-stage prostate cancer. Although there are several ways to remove RB from the cellular machinery, the group found that complete loss, rather than inactivation, of the RB gene was associated with changes in gene networks closely linked to aggressive disease. Surprisingly, the cancer-promoting programme that RB loss unleashed was distinct from the cell-cycle control genes that RB is best known for controlling.
The new findings hold great promise for further clinical development and application. First, the research demonstrates that RB status can be tracked using cell-free DNA samples, an approach referred to as “liquid biopsy,” in prostate cancer patient samples. This method will facilitate the analysis of patient tumours and the selection of the most appropriate therapy based on the individualized features of each patient’s cancer subtype. Multiple clinical trials are now underway in Philadelphia that will determine the impact of RB status as a means to guide more precise cancer therapy.
“Unlike breast cancer, all prostate cancers are currently treated in an identical fashion. This discovery, and the clinical trials we have underway, suggest that RB status might be used as means to stratify patients into more effective treatment regimens,” said Wm. Kevin Kelly, DO, Leader of the SKCC Prostate Cancer Programme.
Sidney Kimmel Cancer Centerhttps://tinyurl.com/y9z38zvg