PRESS-NEWS.org - Press Release Distribution
PRESS RELEASES DISTRIBUTION

Why some melanoma patients do not respond to immunotherapy

2021-03-01
(Press-News.org) NEW YORK, NY (March 1, 2021)--By harnessing the immune system against cancer, immunotherapies have revolutionized the way some types of cancer are treated. But most patients--across cancer types--do not respond, and in most cases, scientists are at a loss as to why.

Researchers at Columbia and MIT have created a new technique that can uncover nearly all of the tricks cancer cells use to evade immunotherapies, which could lead to the development of more effective treatments.

The researchers tested their new technique with cancer cells and matching immune cells from melanoma patients and identified previously unknown resistance mechanisms to immune checkpoint inhibitors, a powerful and widely used class of immunotherapy drugs.

The findings were published online March 1 in Nature Genetics.

Immunotherapies fail or stop working in two-thirds of melanoma patients  

Immune checkpoint inhibitors are drugs that are designed to release the "brakes" that prevent the immune system from operating at full power and attacking the cancer cells.

"With drugs called immune checkpoint inhibitors, we're now getting as close as we have ever been to curing one-third of patients with metastatic melanoma, even at a stage when the disease has spread throughout the body," says study leader Benjamin Izar, MD, PhD, assistant professor of medicine at Columbia University Vagelos College of Physicians and Surgeons.

"So the question is, what is happening in the other two-thirds of patients?" Izar says. "What are the mechanisms of intrinsic or adaptive drug resistance?"

In a previous study published in Cell in 2018, Izar and his team identified 250 genes in metastatic melanoma cells that allow them to evade the immunotherapy. The new study was devised to provide a systematic way to functionally decipher how each of those genes contributes to immunotherapy resistance. 

First Test of CRISPR Tool

The study is the first test of a new tool that combines two advanced technologies--CRISPR gene editing and single-cell RNA and -protein sequencing--in a way that allows researchers to determine the full landscape of how cancer cells can evade the immune system.

Using CRISPR, the researchers inactivated those 250 genes--one by one but in a pooled fashion--to create a mixture of 250 batches of melanoma cells, each with a different mutation. The entire heterogenous population of "edited" cancer cells was then exposed to T cells--the immune cells unleashed by checkpoint inhibitors in patients. 

Cells that resisted being killed by T cells were isolated, and a snapshot of all active processes within these cells was measured using single-cell RNA and protein profiling, providing a high-resolution molecular map of several gene perturbations resulting in immune escape.

"Our approach is unique in that we study these mechanisms in patient-derived models, and rather than looking at how a gene changes a cell's phenotype one gene at a time, we were able to study many genes with potential roles in drug resistance in patients in one sweep. It's the first time that such tools have been used at such a large scale," says Izar.

All told, close to a quarter million cells were analyzed. Computational biology tools, developed by Izar and co-senior author Aviv Regev, PhD, professor of biology at MIT, were employed to make sense of this tremendous data set.

New and Old Resistance Mechanisms Identified

The analysis identified new mechanisms of resistance to immunotherapy along with mechanisms that were previously known. "Basically, we recovered the majority of known mechanisms described over the last 10 years--validating that our approach works and giving us confidence that the new findings are important," Izar says.

"We also uncovered many new mechanisms of resistance," says Johannes C. Melms, MD, a postdoctoral fellow in the Izar lab and the study's co-first author (with Chris J. Frangieh, a doctoral student at MIT). 

One of the new resistance mechanisms involves a gene called CD58. "Our data suggests that loss of CD58 in melanoma cells confers immune escape through three potential mechanisms: impairing activation of T cells, reducing the ability of T cells getting into the tumor, and increasing the production of PD-L1," Melms says. "Because the CD58 gene is not mutated per se but rather just turned off, it raises the possibility that therapies that turn it on could overcome drug resistance in some patients." 

The researchers plan to develop therapies to improve response to immunotherapies based on this finding. 

Izar and his team expect to learn more about resistance to immunotherapy from the study data. "CD58 is just one of many genes that warrant a closer look," Izar says.

In future experiments, the researchers plan to inactivate various combinations of cancer cell genes at once. "In this study, we looked at what happens to cells when only one gene is inactivated," he says. "But it's likely that no single gene is sufficient to confer all the types of resistance to immunotherapy that we see in clinical practice."

The study focused on melanoma, but the same approach could be used to study resistance to immunotherapy in many other forms of cancer, the researchers note. 

INFORMATION:

More Information

The study is titled "Multi-modal pooled Perturb-CITE-Seq screens in patient models define novel mechanisms of cancer immune evasion." 

The other contributors: Pratiksha I. Thakore (MIT), Kathryn R. Geiger-Schuller (MIT and Dana-Farber Cancer Institute), Patricia Ho (Columbia), Adrienne M. Luoma (Dana-Farber), Brian Cleary (MIT), Livnat Jerby-Arnon (MIT and Dana-Farber), Shruti Malu (Dana Farber), Michael S. Cuoco (MIT), Maryann Zhao (MIT), Casey R. Ager (Columbia), Meri Rogava (Columbia), Lila Hovey (MIT), Asaf Rotem (Dana Farber and Immunitas Therapeutics, Waltham, MA), Chantale Bernatchez (MD Anderson Cancer Center), Kai W. Wucherpfennig (Dana Farber), Bruce E. Johnson (Dana Farber), Orit Rozenblatt-Rosen (MIT and Dana Farber), and Dirk Schadendorf (University Hospital Essen and German Cancer Consortium).

This work was supported by the Koch Institute-Dana-Farber/Harvard Cancer Center Bridge Project Grant, the Klarman Cell Observatory, Howard Hughes Medical Institute, NHGRI Center of Excellence in Genome Science, the Center for Cell Circuits, National Institutes of Health (grants K08CA222663, U54CA225088, F32AI138458, R01CA238039, P01CA163222, P30CA013696, and T32GM007367), the Burroughs Wellcome Fund Career Award for Medical Scientists, the Louis V. Gerstner Jr. Scholars Program, the Velocity Fellow Program, a CRI Irvington Fellowship, the Eric and Wendy Schmidt postdoctoral program, the Burroughs Wellcome Fund Career Award at the Scientific Interface, the Ludwig Center for Cancer Research at Harvard, and the Broad Fellows.

Conflict of interest statement: Av.R. is a co-founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas, and until July 31, 2020, was a member of the scientific advisory boards of ThermoFisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics, and Asimov. Since August 1, 2020, Av.R. has been an employee of Genentech. B.I. is a consultant for Merck and Volastra Therapeutics. B.E.J. is on the scientific advisory board of Checkpoint Therapeutics. Since November 16, 2020, K.G.S. and O.R.-R. have been employees of Genentech. As.R. is a consultant to eGenesis, a member of NucleAI's scientific advisory board, and an equity holder in Celsius Therapeutics. Since August 31, 2020, As.R. has been an employee of AstraZeneca. 



ELSE PRESS RELEASES FROM THIS DATE:

Black Americans report high levels of vaccine hesitancy

2021-03-01
Black Americans have a high level of vaccine hesitancy and mistrust of COVID-19 vaccines, including among Black health care workers, according to a new RAND Corporation survey. Those who expressed vaccine hesitancy also showed high levels of overall mistrust in the vaccine, concerns about potential harm and side effects, and lack of confidence in vaccine effectiveness and safety. Participants in the RAND survey reported higher trust in COVID-19 information from health care providers and public health officials than from elected local and federal officials. The findings are based on a survey ...

4D bioengineering materials bend, curve like natural tissue

4D bioengineering materials bend, curve like natural tissue
2021-03-01
Tissue engineering has long-depended on geometrically static scaffolds seeded with cells in the lab to create new tissues and even organs. The scaffolding material -- usually a biodegradable polymer structure -- is supplied with cells and the cells, if supplied with the right nutrients, then develop into tissue as the underlying scaffold biodegrades. But this model ignores the extraordinarily dynamic morphological processes that underlie the natural development of tissues. Now, researchers at the END ...

Deep dive into bioarchaeological data reveals Mediterranean migration trends over 8,000 years

Deep dive into bioarchaeological data reveals Mediterranean migration trends over 8,000 years
2021-03-01
A team of international researchers led by a Florida State University assistant professor has analyzed reams of data from the Neolithic to Late Roman period looking at migration patterns across the Mediterranean and found that despite evidence of cultural connections, there's little evidence of massive migration across the region. "Because of the prevailing scholarly attitude of the 'connected' Mediterranean -- one with high degrees of mobility and migration that drive the archaeological patterns we see -- we'd imagined we'd see comparatively high levels of migration reflected in the strontium isotope data," said Thomas Leppard, assistant professor of anthropology at Florida State. "That instead ...

A research group proposes six guidelines for managing the impacts of invasive species

A research group proposes six guidelines for managing the impacts of invasive species
2021-03-01
 Invasive alien species, defined as animals and plants that breed and disperse in a landscape beyond their native range, have negative environmental, social, and economic impacts. One example among many is the forage grass genus Brachiaria, originally African and introduced to Brazil to form cattle pasture. It has become a major threat to the survival of native species and biodiversity at several spatial scales.  Complete eradication of invasive species is often impracticable. Attempts to do so have had undesirable consequences and even been damaging because merely withdrawing an invasive ...

Noisy brain activity contributes to aging-related navigation impairments

Noisy brain activity contributes to aging-related navigation impairments
2021-03-01
Too much activity in the hippocampus may cause navigation impairments seen in aging adults, according to new research published in JNeurosci. Spatial navigation is one of the cognitive abilities that declines sharply in old age. Older adults often have difficulty navigating new environments and will choose to stick with familiar ones. Plus, key regions in the brain's navigation circuit are some of the first affected by Alzheimer's disease. In a recent study, Diersch et al. examined the neural mechanism behind this decline in spatial learning. In the study, younger ...

Addressing a complex world of pain in a single gene difference

2021-03-01
A single letter difference in a single gene, inherited from both parents, spells a lifetime of anemia and pain for 20 million people, mostly of African ancestry, worldwide. Sickle cell disease (SCD) causes red blood cells to assume a sickle shape and jam in capillaries, cutting off oxygen to lungs, brain, bones and other organs. Despite the single genetic origin of SCD, each person's disease experience and even life expectancy depend upon where they live, and the social, physical and environmental factors they encounter. Now, a new review published by Wiley in the journal Advanced Genetics proposes that it is ...

Scientists describe 'hidden biodiversity crisis' as variation within species is lost

Scientists describe hidden biodiversity crisis as variation within species is lost
2021-03-01
The rapid loss of variation within species is a hidden biodiversity crisis, according to the authors of a new study looking at how this variation supports essential ecological functions and the benefits nature provides for people. Published March 1 in Nature Ecology and Evolution, the study highlights the need to better understand and conserve variation within species in order to safeguard nature's contributions to people. "Biodiversity means more than the number of species, and when we focus on species-level extinctions we are missing part of the story," said corresponding author Eric Palkovacs, professor of ecology and evolutionary biology at UC Santa Cruz. "Intraspecific variation is a neglected aspect of biodiversity, ...

Reinforced by policies, charters segregate schools

2021-03-01
ITHACA, N.Y. - The expansion of charter schools in the 2000s led to an increase in school segregation and a slight decline in residential segregation, according to new research from Cornell University providing the first national estimates of the diverging trends. According to the study, the average district to expand charter school enrollment between 2000 and 2010 experienced a 12% increase in white-Black school segregation and a 2% decrease in white-Black residential segregation. The patterns moved in opposite directions, the research found, because charter ...

Potential target for treating many cancers found within GLI1 gene

2021-03-01
Scientists from the Stanley Manne Children's Research Institute at Ann & Robert H. Lurie Children's Hospital of Chicago found that a region within the DNA of the cancer-promoting GLI1 gene is directly responsible for regulating this gene's expression. These findings, published in the journal Stem Cells, imply that this region within GLI1 could potentially be targeted as cancer treatment, since turning off GLI1 would interrupt excessive cell division characteristic of cancer. "From previous research, we know that GLI1 drives the unrelenting cell proliferation that is responsible for many cancers, and that this gene also stimulates its own expression," says co-senior author Philip Iannaccone, MD, PhD, Professor Emeritus at the Manne Research Institute at Lurie Children's and Northwestern ...

Natural product isolated from sea sponge tested against cancer cells

Natural product isolated from sea sponge tested against cancer cells
2021-03-01
Scientists from Far Eastern Federal University (FEFU) together with Russian and German colleagues, continue studying antitumor compounds synthesized based on bioactive molecules isolated from a sea sponge. One of them fights cancer cells resistant to standard chemotherapy, and at the same time has an interesting dual mechanism of action. A related article appears in Marine Drugs. Scientists have tested the biological effect of the marine alkaloid 3,10-dibromofascaplysin on various prostate cancer cells, including those resistant to standard docetaxel-based chemotherapy. ...

LAST 30 PRESS RELEASES:

Impact of synbiotic supplements on the gut microbiome and overall health of penguins

Promising advances in organosilica membranes for separating organic liquid mixtures

Cell phone video technology unveils new method for analyzing walking and gait

Ancient isolation’s impact on modern ecology

Synaptic protein change during development offers clues on evolution and disease

How commercial rooftop solar power could bring affordable clean energy to low-income homes

Taking a closer look at pulmonary fibrosis genetics

Cats with MDR1 mutation at risk of severe reactions to popular medication

IOP Publishing and IPEM mandate reporting of sex and gender in research 

Dogs trained to detect trauma stress by smelling humans’ breath

Electronic device thermal management made simpler and slightly better!

Study: Dangerous surgical site infections can be reduced with simple prevention protocol

Genetic testing of patients with atrial fibrillation can alert clinicians to potential development of life-threatening conditions

Artificial Intelligence tool successfully predicts fatal heart rhythm

What progress has China made in agriculture green development over the past five years?

ALMA finds new molecular signposts in starburst galaxy

Open waste burning linked to air pollution in Northwestern Greenland

Google Street View reveals how built environment correlates with risk of cardiovascular disease

Connecting the dots to shape growth forces

Parental avoidance of toxic exposures could help prevent autism, ADHD in children, new study shows

Trends in the incidence of renal replacement therapy due to rapidly progressive glomerulonephritis in Japan, 2006–2021

Olympics not likely to swallow up skateboarding’s subversive nature into its corporate spectacle, study says

Looking after the NHS workforce must be a top priority, say experts

Prolonged use of certain hormone drugs linked to increased brain tumor risk

Delirium a ‘strong risk factor’ for dementia among older people

People experiencing homelessness more likely to develop dementia at younger ages, study finds

Can metalens be commercialized at a fraction of the cost?

Reclaim ‘wellness’ from the rich and famous, and restore its political radicalism, new book argues

Curtin research unlocks supernova stardust secrets

New documents reveal patient safety concerns over strike day cover

[Press-News.org] Why some melanoma patients do not respond to immunotherapy