Washington: Cancer researchers have completed one of the most comprehensive studies of the cells inside melanoma brain metastases.Columbia researchers have now completed one of the most comprehensive studies of the cells inside melanoma brain metastases, uncovering details that could spur the development of a new generation of therapies."Brain metastases are extremely common in patients with melanoma, but we have only had a rudimentary understanding of the underlying biology," says study leader Benjamin Izar, MD, PhD, assistant professor of medicine at Columbia University Vagelos College of Physicians and Surgeons. "Our study gives us new insights into the genomics, immunology, and spatial organization of these tumors and serves as a foundation for further discovery and therapeutic exploration."The findings were published online in Cell.Innovative methods allow for deeper analysisTo begin understanding why melanoma brain metastases evade current treatments, Izar and his team needed to invent new techniques for performing single-cell genetic analyses of frozen brain samples."Such studies are typically performed on fresh brain samples, which are in short supply, drastically limiting the number of tumors that can be analyzed. In contrast, we have many frozen melanoma samples in our tissue bank," Izar says."This innovation also allowed us to analyze tissues from patients who had not been treated, letting us see the biology of the tumor and its microenvironment before they're altered by therapy."Therapeutic targets revealedWith metastatic tumors from several dozen melanoma patients, Izar and his colleagues analyzed the genes expressed in more than 100,000 individual cells.The analysis revealed that melanoma brain metastases are more chromosomally unstable than melanoma metastases in other parts of the body."Chromosomal instability is the perpetual gain and loss of large chromosomal fragments; this process triggers signaling pathways that make cells more likely to spread and better able to suppress the body's immune response," says Johannes C. Melms, MD, a molecular postdoctoral fellow in the Izar lab and one of the study's first authors.These pathways could be important therapeutic targets. "Several experimental drugs that reduce chromosomal instability are going to be tested in humans soon," Melms says. "We now have a rationale to evaluate these drugs in patients with melanoma metastases in the brain."&nbsp;Hiding from immune systemThe researchers also uncovered two other characteristics of melanoma brain metastases that may help to hide the cells from the patient's immune system. The researchers found that the metastases alter immune cells, specifically macrophages and T cells, in the tumor microenvironment in a way that promotes cancer growth. And they found that the cells adopt a neuronal-like state inside the brain. "It's possible that these changes help tumor cells adapt and survive in their new environment while avoiding ensuing immune responses," says Jana Biermann, PhD, a computational postdoctoral fellow in the Izar lab and one of the study's first authors.First spatial analysisFinally, the researchers were able to perform the first spatial analysis of melanoma brain metastases, by analyzing and piecing together analyses of multiple slices of the tumors much the way a CT scanner creates three-dimensional images."It turns out there's quite a bit of geographic variability from one tumor to the next and even within a given tumor, in terms of metabolic and immune pathways," says Izar."We are just beginning to understand how to think of spatial variability, but it's clear that this will be key to increasing chances for complete tumor responses to novel therapies."&nbsp;—ANI

 Cancer researchers have completed one of the most comprehensive studies of the cells inside melanoma brain metastases.

Study: New Insights Into Melanoma Brain Metastases

Washington: According to a new study by researchers at Emory University in Atlanta, the use of broad-spectrum antibiotics in mice with malignant melanoma, an aggressive form of skin cancer, accelerated their metastatic bone growth.
This likely happened because the drugs depleted the mice's intestinal flora and weakened their immune response.
The findings underscore the importance of the gut microbiome in overall health and suggest that doctors should carefully weigh the gastrointestinal effects when they use antibiotic therapies while treating cancer or other diseases, said one of the study's authors, Subhashis Pal, Ph.D., a postdoctoral fellow in endocrinology at the Emory University School of Medicine.
"Any disease or therapy that harms the gut microbiome could have a negative impact on our health," said Dr. Pal, who presented the report today at the annual meeting of the American Society of Bone and Mineral Research in Austin, Texas, USA.
"In our study we found that the gut microbiome restrains the progression of melanoma bone lesions in mice by promoting the expansion of intestinal natural-killer (NK) cells and T helper (Th1) cells and enhancing their migration to the tumor site," Dr. Pal said. "Using oral antibiotics depleted the gut microbiome and reduced the population of intestinal NK cells and Th1 cells. This made the mice more vulnerable for tumor growth. They had a higher melanoma tumor burden than control mice whose gut microbiomes were intact."
Osteolytic bone metastasis is a complication of malignant melanoma. The researchers hypothesized that using antibiotics to deplete the gut microbiome of mice would affect their intestinal immune cells and thus alter their immune response, leading to accelerated bone metastasis. They injected B16-F10 melanoma cells into the hearts and bones of mice that had been treated with broad-spectrum antibiotics. As predicted, the antibiotic injections accelerated bone metastatic growth in those mice, compared with control mice that had not received the shots.
The study revealed the mechanism for the metastatic growth of melanoma. Flow cytometric analysis of Peyer's patches and bone-marrow cells within tumor lesions revealed that microbiome depletion prevented the melanoma-induced expansion of intestinal NK and Th1 cells and their migration from the gut to tumor-bearing bones. Direct measurement of NK and Th1 cells migration using Kaede mice, a strain expressing a photo-convertible fluorescent protein that allows direct tracking of intestinal lymphocytes, revealed that antibiotics decreased by about eightfold the migration of NK and Th1 cells from the gut to the tumor site.
When NK cells and Th1 cells leave the gut as part of the body's immune response, the process is mediated by S1PR5 and S1PR1 receptors. Pharmacological blockade of the cells' migration via the receptors -- involving S1PR5 with NK cells, or S1PR1 with Th1 cells -- mimicked the effects of antibiotics. The blockade prevented expansion of NK cells and Th1 cells in the bone marrow and caused accelerated bone metastasis growth.
The influx of circulating NK and Th1 cells to the tumor site is directed by the chemokine ligand CXCL9, which is expressed by bone-marrow cells, and CXCR3, which is expressed by NK and Th1 cells. Global deletion of CXCR3 or antibody neutralization of CXCL9 decreased the frequency of tumor NK and Th1 cells and increased tumor growth.
This study strongly indicates that microbiome modifications induced by antibiotics might have negative clinical consequences not only with melanoma, but with other diseases as well, Dr. Pal said. "For example, inflammatory bowel disease, or other gut conditions that create inflammation, can lead to increased Th17 cells, TNF producing cell numbers in the gut, which ultimately has a negative impact on our bone health. Similarly, we have seen that in a murine model of surgical menopause, reduced levels of estrogen cause bacterial metabolites to pass more easily through the gut barrier and hyperactivate the immune system. As a result, the number of intestinal and bone marrow cytokine producing T cells rises, largely contributing to the development of bone loss."
Dr. Pal added: "We should be very much careful with our gut microbiome, and of the unforeseen adverse consequence of antibiotic regimens. Conversely, probiotics can play a major role to maintain healthy gut microbiome, and better overall health." —ANI

According to a new study by researchers at Emory University in Atlanta, the use of broad-spectrum antibiotics in mice with malignant melanoma, an aggressive form of skin cancer, accelerated their metastatic bone growth.

Antibiotics Might Worsen Melanoma By Depleting The Gut Microbiome: Study

London: Eating a Mediterranean diet, rich in fibre, mono-unsaturated fatty acids and polyphenols, has been associated with improved immunotherapy response rates and progression-free survival in advanced melanoma patients, says a new report.
The study, presented at UEG Week 2022, has found that diet plays an important role in the success of immunotherapy and trials are being expanded to investigate outcomes for different tumour types, including digestive cancers.
"Our study underlines the importance of dietary assessment in cancer patients starting ICI treatment and supports a role for dietary strategies to improve patient outcomes and survival," said researcher Laura Bolte from the University Medical Center Groningen, Netherlands.
For the study, the team recorded the dietary intake of 91 patients with advanced melanoma, who were treated with ICI drugs and monitored their progress with regular radiographic response check-ups.
As well as having a significant association with overall response rate, a Mediterranean diet was significantly associated with progression-free survival at 12 months.
The study also found that eating whole grains and legumes reduced the likelihood of developing drug-induced immune-related side effects, such as colitis. In contrast, red and processed meat was associated with a higher probability of immune-related side effects. —IANS

 Eating a Mediterranean diet, rich in fibre, mono-unsaturated fatty acids and polyphenols, has been associated with improved immunotherapy response rates and progression-free survival in advanced melanoma patients, says a new report.

This Diet Improves Immunotherapy Response Rates, Progression-Free Survival In Advanced Melanoma

Solna: Long-lasting killer cells are present in our skin and act as a defence against intruders. Researchers from Denmark's University of Copenhagen and Sweden's Karolinska Institutet have now discovered how these cells are formed and demonstrated that higher concentrations of memory killer cells in tumour tissue are associated with a higher survival probability for melanoma patients. The work was published in the journal Immunity. Certain immune T cells called tissue-resident memory cells are formed locally in the skin and other tissue, and protect against infections that they have encountered before. Some of them express proteins that enable them to kill infected cells. These "memory killer cells" can also contribute to the inflammatory skin disorders vitiligo and psoriasis. Recent research has shown that they are also involved in the body's immune response to various cancers. The memory killer cells have been shown to respond to immunotherapy, a Nobel Prize-winning cancer therapy involving the tweaking/activation of the immune system. Immunotherapy is normally administered as a complement to other cancer treatments, and there is considerable variation in how patients respond to it. "We don't know so much about how and why memory killer cells are formed in the skin and what it means for cancer patients," says Professor Yenan Bryceson at the Department of Medicine (Huddinge), Karolinska Institutet. "Finding out how these cells develop enables us to contribute to the development of more efficacious immunotherapy for diseases like melanoma." The study charted the development of memory killer cells in human skin, performed as a collaborative effort between KI researchers Beatrice Zitti and Elena Hoffer. The researchers isolated T cells from the skin and blood of healthy volunteers and used advanced techniques to examine gene activity and expression of different proteins. This allowed them to identify T cells in the blood with the potential to develop into memory killer cells in skin or other tissues. After knocking out specific genes, they could also demonstrate which genes are required for the maturation of memory killer cells in tissue. More effective immunotherapy The researchers then went on to study tumour samples from melanoma patients and found that those with a higher rate of survival also had a larger accumulation of epidermal memory killer cells. "We've been able to identify several factors that control the formation of memory killer cells, which play an important part in maintaining a healthy skin," says Liv Eidsmo, dermatologist and professor at the University of Copenhagen in Denmark and researcher at Karolinska Institutet in Sweden. "There's a fine balance between effective protection against tumours and infections in the skin and contribution to inflammatory diseases like vitiligo and psoriasis." The researchers now aim to harness their findings to optimise the immunotherapy-induced T-cell response to make it even better at eliminating cancer cells in tissues. The study was conducted in collaboration with the Karolinska University Hospital, Nordiska Kliniken and Vrinnevi Hospital. It was financed by grants from Novartis, the EU (Marie Sklodowska-Curie Actions), KI Foundations and Funds, the Swedish Research Council, the Ragnar Soderberg Foundation, the Swedish Medical Society, Region Stockholm (ALF scheme), the Swedish Psoriasis Foundation, the Swedish Dermatology Foundation, the Swedish Cancer Society, the Goran Gustafsson Foundation, Stockholm City Council, the Karolinska Institutet Centre for Innovative Medicine (CIMED) and the Knut and Alice Wallenberg Foundation. There are no reported conflicts of interest. —ANI

Long-lasting killer cells are present in our skin and act as a defence against intruders. Researchers from Denmark's University 

Memory Killer Cells May Improve Melanoma Patients' Chances Of Survival: Study

Washington: A new study sponsored by McGill University investigates why persons living in Atlantic regions are more likely to develop melanoma than other Canadians, providing lessons on skin cancer prevention for the entire country. Rates of melanoma, a deadly form of skin cancer, have been rising globally, including in Canada. Current estimates indicate that up to 1 in 3 Canadians will develop some form of skin cancer during their lifetime. While some Atlantic provinces such as Prince Edward Island (PEI) and Nova Scotia have the highest incidence rate of melanoma in the country, neighbouring provinces like New Brunswick and Newfoundland and Labrador have rates below or comparable to the Canadian average. To find out why, the researchers compared UV exposure and behaviours among different groups in Atlantic Canada based on income, education, and gender, among other factors. Higher-income individuals more at risk for melanoma The study found that higher-income individuals had an increased risk of melanoma. Risk factors contributing to this include more lifetime sun burns, tanning bed use, and being tanned. Similarly, individuals with university education had higher rates of recreational sun exposure but were less likely to use tanning beds. "A higher socio-economic status is known to be associated with more vacations in sunny climates and recreational tanning, which likely ultimately drives melanoma incidence in this population," highlights Dr. Ivan Litvinov, an Associate Professor in the Department of Medicine and Chair of the Dermatology Division at McGill University. However, the study also showed that individuals earning less than $50,000 a year were more likely to work outdoors and experience occupational sun exposure, placing them at a higher risk of developing skin cancer. These findings suggest that policies to protect outdoor workers could help reduce melanoma risk, say the researchers. Looking at differences between men and women, the researchers found that women had less sun exposure and practiced more sun protection compared to men. Men were more likely to report more lifetime sunburns as well as occupational and recreational sun exposure. They also had higher rates of melanoma and other skin cancers. Nevertheless, women tended to wear fewer long-sleeve shirts and frequented tanning beds more. These behaviours, the researchers say, may explain findings in a previous study that show women are more likely to develop melanoma in their extremities. When it comes to skin cancer prevention, their study found that men express more negative beliefs toward sunscreen use than women. Consistent with this, women were more concerned about new moles and were more likely to seek medical advice from a family physician. The researchers say these behavior patterns may account for the overall lower melanoma incidence and mortality in women. Putting sun protection knowledge into practice The findings also show that people living in the most high-risk communities of PEI and Nova Scotia had more sunburns and sun exposure compared to people in regions like Newfoundland and Labrador. Surprisingly, those living in these high-risk communities had more knowledge of sun protection and melanoma awareness as well. "To prevent skin cancer many Canadians really need to act on the knowledge they already have. Applying sunscreen is one of the effective ways to prevent skin cancer," says Dr. Litvinov. Public health efforts aimed at reducing skin cancer should be tailored to target specific demographic groups, the researchers say. "You need to have a different sun protection message when you're talking to a single young man versus a mother of three children," says Dr. Litvinov. "Governments also have a direct role to play in combatting rising rates of melanoma. It's projected that the financial burden of skin cancer to the Canadian healthcare system could rise to one billion annually by 2030," he adds. "Canada should follow in the footsteps of many countries that have removed sales tax on sunscreen to promote their use." —ANI

A new study sponsored by McGill University investigates why persons living in Atlantic regions are more likely to develop melanoma than other Canadians

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Study: New Insights Into Melanoma Brain Metastases

Inam Ansari

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Tag : Melanoma

Study: New Insights Into Melanoma Brain Metastases

Inam Ansari

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