Breaking News
November 14, 2018 - Study shows novel strategy to reduce breast cancer bone metastasis
November 14, 2018 - Empowering the NHS through Industry Partnerships
November 14, 2018 - One size does not fit all in obesity treatment, study finds
November 14, 2018 - Seeking ways to prevent ‘secondary cataracts’
November 14, 2018 - Change Within the Eye May Be Early Warning for Macular Degeneration
November 14, 2018 - Study of 500,000 people clarifies the risks of obesity
November 14, 2018 - Ultrasound releases drug to alter activity in targeted brain areas in rats | News Center
November 14, 2018 - Umass Amherst researchers battle against youth suicide in rural Alaska Native communities
November 14, 2018 - Cancer stem cells depend on amino acid metabolism, and it’s proving to be their Achilles’ heel
November 14, 2018 - Epigenetic link found between prenatal exposure to maternal smoking and offspring’s cardio-metabolic health
November 14, 2018 - Meditation, music may change biomarkers of cellular aging and Alzheimer’s disease in older adults
November 14, 2018 - Multidisciplinaryresearch teams selected to study age-related brain disorders
November 14, 2018 - The Current issue of “The view from here” is concerned with Informatics
November 14, 2018 - Researchers identify tool to help transgender women have a more authentic voice
November 14, 2018 - Four faculty members appointed to endowed professorships | News Center
November 13, 2018 - Research finds strongest evidence yet that obesity causes depression
November 13, 2018 - Researchers compare stools of breastfed and formula-fed infants
November 13, 2018 - Entasis Therapeutics Announces Zoliflodacin Phase 2 Results Published in The New England Journal of Medicine
November 13, 2018 - Gene changes driving myopia reveal new focus for drug development
November 13, 2018 - $6 million grant to support study of preeclampsia, atherosclerosis links | News Center
November 13, 2018 - Beneficial gut microbes metabolize high-fiber diet to improve heart health in mouse model
November 13, 2018 - Excessive use of social media through visual postings linked to increase in narcissistic traits
November 13, 2018 - Study finds why obesity both fuels cancer growth and helps immunotherapy to kill tumors
November 13, 2018 - Women prefer and invest more in daughters, while men favor sons
November 13, 2018 - With hospitalization losing favor, judges order outpatient mental health treatment
November 13, 2018 - Transgenic rat model may provide new insights into cerebral amyloid angiopathy
November 13, 2018 - Study identifies factors tied to greater risk of advanced liver disease in cystic fibrosis patients
November 13, 2018 - Risk of blindness among premature babies with low levels of blood platelets
November 13, 2018 - A new strategy for combatting antibiotic-resistant infections
November 13, 2018 - Study aims to find which outreach method is more effective at improving cancer screening rates
November 13, 2018 - Insufficient sleep duration linked with unhealthy lifestyle profile among children
November 13, 2018 - IIASA researchers introduce new, simple measure for human wellbeing
November 13, 2018 - Magnetic nanosprings used as targeted drug delivery agents for anticancer therapy
November 13, 2018 - Scientists examine FCMs containing silver nanoparticles
November 13, 2018 - Failed DNA repair triggers chromosomal chaos
November 13, 2018 - Study shows new emerging role of osteopontin in HCV-related hepatocellular carcinoma
November 13, 2018 - Food insecurity during pregnancy linked to severity of neonatal abstinence syndrome
November 13, 2018 - Majority of Americans are concerned about health threat posed by antibiotic resistance
November 13, 2018 - Addition of Elotuzumab Ups PFS in Refractory Multiple Myeloma
November 13, 2018 - Study finds women with pregnancy-related nausea, vomiting use marijuana more
November 13, 2018 - Lethal heart rhythm more likely to be found in patients with common heart failure
November 13, 2018 - Study provides new clues to origin and development of multiple sclerosis
November 13, 2018 - Climate change could pose threat to male fertility
November 13, 2018 - Researchers discover how mitochondria deploy a powerful punch against disease-causing bacteria
November 13, 2018 - AHA: Traumatic Childhood Could Increase Heart Disease Risk in Adulthood
November 13, 2018 - Feeling the Burn? | NIH News in Health
November 13, 2018 - Women’s birth canals in Kenya, Korea, Kansas not the same: study
November 13, 2018 - Fecal microbiota transplantation effective against ICI-associated colitis
November 13, 2018 - New physical activity guidelines released that urge people to “move more”
November 13, 2018 - Angiotensin receptor blockers improve sodium excretion in blacks
November 13, 2018 - New project seeks to address alarming injury rate in youth footballers
November 13, 2018 - Fish oil or omega 3 fatty acid supplements can prevent heart attacks finds study
November 13, 2018 - The Human Heart-in-a-Jar That Could One Day Replace Animal Testing
November 13, 2018 - Treat patients’ partners without a doctor visit
November 13, 2018 - Belgian beer landscape mapped using scientific insights
November 13, 2018 - ‘Master key’ gene has links to both ASD and schizophrenia
November 13, 2018 - Gladstone scientists gain new insights into the aging brain
November 13, 2018 - Drug therapy can improve outcomes for acutely ill heart patients
November 13, 2018 - Three landmark studies provide better understanding of sudden cardiac arrest
November 13, 2018 - Cholesterol control revised in the latest AHA/ACC guidelines
November 13, 2018 - Vulnerable young teenagers urgently need better sex education, say researchers
November 13, 2018 - Breakthrough research reveals how deadly pneumococcus avoids immune defenses
November 13, 2018 - Researchers discover possible path forward in preventing cancers tied to two viruses
November 13, 2018 - Wishes can help pediatric patients to get better over time
November 13, 2018 - Janssen Reports Positive Topline Results for FLAIR Phase 3 Study of a Novel, Long Acting Injectable Two-Drug Regimen for the treatment of HIV-1
November 13, 2018 - Experimental compound reduces Gulf War illness-like behavior in mice
November 13, 2018 - Small-stature in rainforest populations may be linked to cardiac adaptations
November 13, 2018 - Study shows how pneumococci challenge the immune system
November 13, 2018 - Simple cysts can be safely ignored, study finds
November 13, 2018 - First fully personalized tissue implant engineered from patient’s own materials and cells
November 13, 2018 - FDA Approves Keytruda (pembrolizumab) in Combination with Carboplatin and Either Paclitaxel or Nab-Paclitaxel for the First-Line Treatment of Patients with Metastatic Squamous Non-Small Cell Lung Cancer (NSCLC)
November 13, 2018 - Scientists take big step toward finding non-addictive painkiller
November 13, 2018 - Diabetes medication reduces risk of heart failure hospitalization
November 13, 2018 - Achieving high follow-up rates for violently injured patient population is feasible
November 13, 2018 - Shortage of specific gene ‘silencing’ molecules linked with pediatric low-grade gliomas
November 13, 2018 - Abx-Resistant Enterobacteriaceae Tied to Clinical Failure in UTI
November 13, 2018 - US approves first new type of flu drug in 2 decades
November 13, 2018 - Is zinc the link to how we think? Some evidence, and a word of warning
November 13, 2018 - Dispelling taboos, Michelle Obama talks IVF and miscarriage
November 13, 2018 - Medical experts discuss future challenges of healthcare at HSMA’s inaugural conference
Single-cell analysis reveals how melanoma cells resist immunotherapy

Single-cell analysis reveals how melanoma cells resist immunotherapy

image_pdfDownload PDFimage_print
Single-cell analysis reveals how melanoma cells resist immunotherapy
Credit: Broad Institute of MIT and Harvard

Unleashing the immune system to fight tumors—an approach enabled by immunotherapy—has led to remarkable outcomes in some cancer patients, but in many more, cancer cells evade the treatment and continue to spread. Now, a team led by researchers from Broad Institute of MIT and Harvard and Dana-Farber Cancer Institute has identified a gene expression pattern that human melanoma cells use to resist immunotherapy, and demonstrated a combination therapy approach that could overcome this resistance.

The paper, published today in Cell, appears alongside a companion immunotherapy study led by a separate research team from Broad Institute and Massachusetts General Hospital.

“With additional data, we hope that the methods and specific combination therapy identified in our study could have a real benefit for patients,” said co-senior author Benjamin Izar, an instructor in medicine and melanoma oncologist at Dana-Farber Cancer Institute and postdoctoral fellow at the Broad Institute. He and Aviv Regev, director of the Klarman Cell Observatory at the Broad Institute, professor of biology at MIT, and an HHMI investigator, are co-senior authors on the paper.

“Our team has mapped out a high-resolution landscape of immunotherapy-resistant melanoma,” added Regev. “We’ve discovered a gene expression program that can help predict resistance to immunotherapy before treatment even begins, and a potential way to reverse this program in order to delay or counter that resistance.”

Using single-cell RNA sequencing data, the researchers analyzed thousands of melanoma cells from more than 30 melanoma patients, half of which had exhibited resistance to immunotherapies. The team identified a distinct gene expression pattern that correlated with reduced T cell presence in the tumor and other features of immunotherapy resistance.

By measuring the levels of this “resistance program” before treatment, the team could predict how tumors would respond to immunotherapy—thereby addressing a major clinical challenge in the field of immuno-oncology. This analysis was done in larger independent cohorts of melanoma patients, assembled in collaboration with colleagues at Massachusetts General Hospital and the University of Essen in Germany. And in another patient cohort, the group showed that cancer cells further amplify this program when exposed to immunotherapy.

The resistance program included signals that are hallmarks of immune system evasion. Abnormal cells typically have substances on their surfaces, called antigens, that enable T cells to home in and destroy them. But the resistant tumor cells are able to reduce their antigen levels and hide from the immune system. They also reduce the enzymes attacked by the T cells, rendering an assault ineffective if it does occur. Other genes expressed in this program include those that cause cells to unduly proliferate.

“We found that multiple immune evasion mechanisms, and other hallmarks of cancer growth, are strongly co-regulated with each other in this resistance program,” said Livnat Jerby, a postdoctoral fellow in Regev’s lab and first author on the paper. “Certain mutations in these pathways have already been reported to confer immunotherapy resistance, but here we show that there is a shared regulatory program controlling their expression.”

Once the researchers understood this molecular strategy, they began exploring ways to suppress it and sensitize melanoma tumor cells to immunotherapy. Mining data across hundreds of human cell lines, the team predicted that a class of cancer drugs called CDK4/6 inhibitors, which are already known to suppress cell proliferation, could in part reverse the resistance program in cells.

In a mouse model of extremely immunotherapy-resistant melanoma—which expressed the newly discovered resistance program at high levels—the CDK4/6 inhibitors dramatically improved responses to immunotherapy, and the combination approach significantly slowed or eradicated tumors in roughly half the mice.

“It’s unclear what all of CDK4’s activities might actually be, but our data indicate that it could be a ‘master regulator’ of this resistance program,” said Jerby.

Based on this work, the researchers are pursuing a clinical trial to further test their findings. “Our work, along with that of colleagues studying the effects of CDK4/6 inhibitors in breast cancer and other diseases, provides a rationale for exploring combination therapy with immune checkpoint inhibitors,” said Izar. “It’s exciting to see that our work may actually translate back into the clinic and make a difference for patients with resistant melanoma.”


Explore further:
Specific CD8 T cell states may indicate response to immune checkpoint therapy for melanoma

More information:
Livnat Jerby-Arnon et al. A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade, Cell (2018). DOI: 10.1016/j.cell.2018.09.006

Journal reference:
Cell

Provided by:
Broad Institute of MIT and Harvard

About author

Related Articles