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Welcome to the March 19, 2021 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the ӳ����ý and their collaborators.

Combining sequencing methods to understand immunotherapy resistance

Immune checkpoint inhibitors help patients’ immune systems fight cancer, but many patients develop resistance to these inhibitors. Chris Frangieh, Johannes Melms (Columbia), Pratiksha Thakore, Katie Geiger-Schuller, core institute member Aviv Regev (now at Genentech), and Benjamin Izar (Columbia) have created a new screening technology, called Perturb-CITE-seq, to explore the mechanisms underlying this resistance. The method combines genetic perturbation technologies and CITE-seq — a method for profiling gene and protein expression in individual cells. Using this technology, they found that loss of the cell-surface protein CD58 helps melanoma cells evade a patient’s own immune system. Read more in and a ӳ����ý story.

Understanding how kidney cancer dodges the immune system

Drugs that help the immune system fight cancer are a leading treatment for advanced kidney cancer, but not all patients respond, and many develop resistance. In two Cancer Cell papers, researchers from ӳ����ý and Dana-Farber Cancer Institute investigated how the immune system responds to kidney cancer, in the presence and absence of treatment. In , David Braun, Kelly Street (DFCI), Toni Choueiri (DFCI), institute member Catherine Wu of the Cancer Program, and colleagues identified an “immune dysfunction circuit” in advanced tumors, in which macrophages and exhausted T cells tag-team to suppress immune function. In the , Kevin Bi, Meng Xiao He, Regev, Toni Choueiri (DFCI), associate member Eliezer Van Allen, and colleagues examined how cancer-immune interactions differ in kidney cancer patients who have undergone treatment with PD-1/PD-L1 checkpoint inhibitors, the most common immunotherapy used in kidney cancer. They saw that treated tumors upregulated transcriptional programs that can suppress the immune system and avoid the blockade — mechanisms that could possibly be targeted by future drugs. Read more in a DFCI press release.

SARS-CoV-2 hijacks metabolic pathways for replication

How coronaviruses, and notably SARS-CoV-2, appropriate metabolic pathways to support viral replication has remained unclear. Yuchen Zhang, Rui Guo, Sharon Kim, Hardik Shah, Shuting Zhang, Matteo Gentili, core institute member and Infectious Disease and Microbiome Program co-director Deborah Hung, institute member and Metabolism Program co-director Vamsi Mootha, associate member Benjamin Gewurz, and others led a new transcriptomic and metabolomic investigation into the lifecycle of SARS-CoV-2. The team found that infected cells are low in glucose and folate, and that the virus co-opts folate and one-carbon pathways to support purine synthesis. Published in , the results suggest that metabolic pathway inhibitors such as methotrexate, an FDA-approved arthritis treatment, could help treat patients hospitalized with COVID-19. Learn more in a Brigham and Women’s Hospital news story.

COVID cooperators

As with all viruses, SARS-CoV-2 relies on host proteins and circuits in order to replicate within host cells. Hasmik Keshishian, Randy Melanson, core institute member Eric Lander (on leave), and institute scientist and Proteomics Platform senior director Steven Carr joined collaborators at Stanford and the University of Würzburg to profile the host proteins that interact with SARS-CoV-2 RNA, collectively dubbed the virus's host interactome. Through a combination of proteomic, functional genetic, and pharmacologic studies, they identified 18 host proteins that bind viral RNA — two of which interfere with viral replication — and 20 compounds that block interactome proteins. Learn more in .

BMI causally associated with COVID-19 severity

Cardiometabolic conditions, especially body mass index (BMI), are associated with increased COVID-19 susceptibility and severity. Associated scientist Aaron Leong (MGH) and research scientist Josep Mercader in the Diabetes Program, and their colleagues statistically analyzed genetic variants associated with 17 cardiometabolic diseases and traits (including diabetes, coronary artery disease, stroke, chronic kidney disease, and BMI) for causal links with positive COVID-19 tests and hospitalization in COVID-19 patients and population controls. In , they reported that BMI is a causal risk factor for COVID-19 hospitalization, and hence, severity. Type 2 diabetes may mediate this relationship but more research is needed. 

A thalidomide analog targets fusion oncoproteins

Avadomide is a novel thalidomide analog with potent antitumor and immunomodulatory activities. Aline Renneville, institute member Benjamin Ebert, and colleagues in the Cancer Program and Proteomics Platform used quantitative mass spectrometry-based proteomic profiling to show that avadomide causes cells to degrade the transcription factor ZMYM2, which is involved in chromosomal rearrangements in some aggressive forms of blood cancers. Appearing in , the work suggests that patients with blood cancers harboring certain ZMYM2 fusion oncoproteins could benefit from avadomide treatment.

Targeting CoQ-deficiency kidney disease

Mutations that deplete mitochondria of the enzyme CoQ lead to kidney cell damage and ultimately organ failure. In , a team led by Eriene-Heidi Sidhom and institute member and Kidney Disease Initiative director Anna Greka explored a molecular pathway involved in this condition. The researchers studied mice with mutations in the gene Pdss2 — causing CoQ deficiency — and, in collaboration with the Metabolomics Platform, identified how this enzyme shortage affects the Braf/Mapk pathway. A compound known as GDC-0879 targeted the Braf pathway and restored kidney cell function, providing a potential treatment strategy. Learn more in a from Eriene and an JCI video.

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