Research Roundup: January 4, 2019

Welcome to the January 4, 2019 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

On a path to effective cancer immunotherapy

Most patients with cancer treated with immune checkpoint blockade (ICB), a type of immunotherapy, either develop resistance to or do not respond to it mostly because of acquired mutations which disrupt the ability of the immune system to recognize tumors. Using CRISPR screening, researchers found that loss of function of a specific enzyme called ADAR1, in tumor cells sensitizes tumors to immunotherapy and also overcomes resistance to ICB. The findings from this study led by Jeffrey Ishizuka, Robert Manguso, and associate member Nicholas Haining — all of the Broad Cancer Program and Dana-Farber Cancer Institute (DFCI) — and collaborators will help point toward potential strategies for effective immunotherapy in the future. Read more in Nature.

A high-resolution gut check

To examine how genomic diversity of gut microbes in childhood impacts later development of the gut microbiome, a team led by Tommi Vatanen and core institute member and Infectious Disease and Microbiome Program (IDMP) co-director Ramnik Xavier and examined data from the DIABIMMUNE study in Finland, Estonia, and Russian Karelia, including nearly 300 children at increased genetic risk for autoimmune disorders. They performed 16S rRNA gene sequencing and metagenomic sequencing of stool samples collected throughout the first three years of life. Described in Nature Microbiology, their high-resolution strain tracking revealed large and highly dynamic microbial pangenomes, especially in the genus Bacteroides, and found that strain diversity has functional consequences.

A hot-headed fight against cold tumors

To battle an immunologically “cold” tumor like glioblastoma, which is hard to treat with immunotherapy, scientists are trying to heat things up by inflaming the environment around the brain cancer cells. Institute member Catherine Wu of DFCI and the Broad Cancer Program, David Reardon (DFCI& and Harvard Medical School), Derin Keskin, Annabelle Anandappa (DFCI), Jing Sun (DFCI), and Broad alum Itay Tirosh (now at the Weizmann Institute of Science) led a trial to create a personalized “neoantigen” vaccine against glioblastoma. Described in Nature, the team’s vaccine safely spurred a response against glioblastoma by generating immune T-cells that migrated into the brain tumor. Read more in this DFCI press release.

Yeast common denominator for drug resistance, virulence may be found in genome

Broad’s senior group leader of fungal genomics, Christina Cuomo, and postdoc José Muñoz (both of the IDMP), along with Anastasia Litvintseva at the Centers for Disease Control and Prevention, led a study on the genomic basis of drug resistance and virulence in Candida auris, a multidrug-resistant (MDR) fungal pathogen responsible for a growing number of outbreaks. The team looked at genome assemblies of each C. auris clade in global outbreak, comparing them with those of related MDR species and the more well-studied pathogen C. albicans. Their findings, published in Nature Communications, identified changes in genes linked to drug resistance and nutrient acquisition, including transporters, lipases, and the drug target ERG11, and mapped how isolates from different clades may be capable of mating.

A 3-in-1 approach for probing noncoding DNA

Methods for studying regulatory elements within the noncoding genome tend to be expensive, labor-intensive, and largely low-throughput. In Nature Communications, Xinchen Wang, associate members Melina Claussnitzer of the Broad Metabolism Program and Beth Israel Deaconess Medical Center, associate member Manolis Kellis of the Broad Epigenomics Program and MIT, and colleagues revealed HiDRA (for High-resolution Dissection of Regulatory Activity), a new approach that merges two sequencing-based assays and a machine learning-based computational tool to characterize enhancers, promoters, and other regulatory DNA segments at high resolution and scale. In cell line experiments, HiDRA allowed the team to study how disease-associated point mutations affect regulatory DNA function, and even highlighted potential new classes of regulatory DNA. Read more in a Broad news story.

Folding function into GWAS

Genome-wide association studies (GWAS) measure DNA variants' (aka SNPs') association with a disease or trait, but do not account for knowledge of what a given variant or DNA region does — functional information that could boost a study's ability to highlight SNP-trait associations. Assocate member Alkes Price of the Harvard T.H. Chan School of Public Health and the Broad Program in Medical and Population Genetics, Gleb Kichaev and Bogdan Pasaniuc of UCLA, and colleagues have developed an analytical approach, dubbed FINDOR (Functionally Informed Novel Discovery Of Risk loci), that uses functional information and polygenic modeling to filter GWAS data. When applied to data from UK Biobank, FINDOR identified hundreds of previously unnoticed SNP associations, without an appreciable rise in false positives. Learn more in the American Journal of Human Genetics.

To learn more about research conducted at the Broad, visit broadinstitute.org/publications, and keep an eye on broadinstitute.org/news.