Tag: melanoma

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Craters on Surface of Melanoma Cells Serve as Sites for Tumour Killing

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Studying these craters could better assess immunotherapy’s success in treating solid tumours

3D structure of a melanoma cell derived by ion abrasion scanning electron microscopy. Credit: Sriram Subramaniam/ National Cancer Institute

Like the surface of the moon, new research published today in Cell finds the existence of craters on the surface of melanoma cells that serve as immune hubs, becoming major sites for tumour killing. These craters could serve as good markers for immunotherapy success.

This research provides insight into a key function of immune check-point blockade (ICB) cancer therapy that was previously unknown. ICB works by re-activating CD8+ T cells against tumours which shrinks and eventually kills the cancer cells. However, what facilitates local tumour killing by the infiltrating CD8+ T cells has remained a mystery.

Using a zebrafish model, researchers were able to monitor the infiltrating CD8+ T cells for up to 24 hours as they moved through the 3D architecture of endogenous melanoma tumours. Zebrafish provide the only tumour model where continuous live imaging over a 24 hour time period is feasible.  

“We found that rather than patrolling the entire tumour surface, CD8+ T cells aggregated in pockets on the melanoma border, forming prolonged interactions with melanoma cells,” says Leonard Zon, MD, Director of the Stem Cell Program at Boston Children’s Hospital and lead investigator of the study. “We termed these pockets Cancer Regions of Antigen presentation and T cell Engagement and Retention (CRATERs) and saw that, following immune stimulation, the CRATERs expanded and facilitated an effective immune response against the tumour.”

Zon, first author Aya Ludin, and the team also discovered CRATERs in human melanoma samples. Moreover, they saw similar structures in human lung cancer, indicating that CRATERs are likely not limited to melanoma and may form in other solid tumours.

To date, efficacy of therapeutic response to ICB therapy has been assessed mainly by estimating the degree of tumour necrosis and fibrosis. Indicators of CD8+ T cells infiltration has been associated with patient survival and treatment outcome, but direct evidence of effective immune cell-tumour cell interaction has been missing.

“Pending thorough clinical verification and taken together with other measurements, CRATERs may serve to more accurately assess the efficacy of an ongoing treatment and improve treatment outcomes,” said Zon.

The research team is now planning a prospective clinical trial to test if CRATERs are the best marker of ICB success.

Source: Boston Children’s Hospital via EurekAlert!

Categories : Cancer Lab Tests and ImagingTags :

At-home Melanoma Testing with Skin Patch Test

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A microneedle patch captures cancer biomarkers in the top-most layer of skin to detect melanoma in animal tissue samples

The newly designed ExoPatch being removed from a sample of mouse skin successfully distinguished melanoma from healthy skin in mice. A gel coating the microneedles picks up cancer indicators from the top-most layer of the skin. Dissolving the gel releases exosomes into a solution, which is then used on a two-lined test strip, similar to an at-home COVID-19 test. Image credit: Jeremy Little, Michigan Engineering.

Melanoma testing could one day be done at home with a skin patch and test strip with two lines, similar to COVID-19 home tests, according to University of Michigan researchers. Developed with funding from the National Institutes of Health, the new silicone patch with star-shaped microneedles, called the ExoPatch, distinguished melanoma from healthy skin in mice.

The patch and test move toward rapid at-home melanoma testing, helping patients catch the most aggressive form of skin cancer early without a biopsy or blood draw.

“The star-shaped needles make puncture easier and less painful, but they are so small that they only go through the top-most layer of the skin, the epidermis, and do not draw blood,” said Sunitha Nagrath, the Dwight F. Benton Professor of Chemical Engineering at U-M and co-corresponding author of the study published in Biosensors and Bioelectronics.

The ExoPatch microneedles, at just 0.6mm long with a width of less than 100 nm (0.0001 mm) at the tip, are coated with a gel that picks up exosomes, tiny packages released by cells, from the interstitial fluid that fills the spaces between cells in the epidermis.

Once thought to be trash ejected from cells for cleanup, exosomes actually contain DNA and RNA fragments that cells use to communicate with each other. Cancer cell exosomes can help tumours spread by preparing tissues to accept tumour cells before arrival, and detecting them can catch cancer earlier than past methods.

The gel that coats the ExoPatch contains a protein called Annexin V that attracts and sticks exosomes to the microneedles’ surface. Once removed from the skin, placing the patch in an acid dissolves the gel, which releases the exosomes into a solution. After dipping a test strip into the solution, two lines form if the sample contains melanoma exosomes, and one line forms for a negative test – the same way an at-home COVID-19 test strip works.

“A fair-skinned person with moles must go to the doctor about every six months to send off a biopsy to see if they’re malignant or benign. With this test, they could instead test at home, get the results right away and follow up with a dermatologist for a positive result,” Nagrath said.

As a first step in the proof-of-concept study, the researchers tested the ExoPatch on a tissue sample of pig skin, which closely resembles human skin in thickness and composition. Using a microscope, they found the microneedles penetrated about 350 to 600nm into the skin. For scale, the epidermis on the human forearm is about 18 300nm thick.

To test whether the ExoPatch could capture melanoma exosomes from skin tissue, the research team tested tissue samples of mouse skin, half from healthy mice and half from mice injected with a fragment of a human melanoma tumour. After a 15-minute application, the ExoPatch was placed under a powerful microscope.

“When looking at microscopy images, I was happy to see how nicely the exosomes adhered to the microneedles and were within the 30 to 150 nanometre size range we expect,” said Scott Smith, U-M doctoral student of chemical engineering and co-lead author of the study.

After confirming the exosomes stuck to the ExoPatch, the researchers dissolved the gel and ran the sample through the test strips. The test successfully distinguished between melanoma and healthy tissues with a 3.5-fold darker line in melanoma samples.

The ExoPatch isolated 11.5 times more exosomal protein from melanoma tissue samples compared to healthy tissue, showing it can specifically target cancerous exosomes.

A pilot study in humans followed by a series of clinical trials will be the next steps to move the technology toward use. Beyond melanoma, the ExoPatch gel coating could be modified to detect exosomes released by other cancers with a solid tumour, including lung, breast, colon, prostate and brain cancer.

“This is the first patch designed to capture disease-specific exosomes from fluid under the skin. The potential applications are huge,” said Nagrath.

Source: University of Michigan

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Existing Drug Class May Help Patients with Immunotherapy-resistant Melanoma

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3D structure of a melanoma cell derived by ion abrasion scanning electron microscopy. Credit: Sriram Subramaniam/ National Cancer Institute

Increased activity in a specific biological pathway may explain why many patients with a deadly form of skin cancer do not respond to the latest cancer treatments, a new study shows.

Publishing in the journal Cancer Research, the study featured data generated from experiments with human tissues and cells from patients with advanced melanoma that were implanted into mice. Results uncovered therapeutic targets that could limit melanoma growth in patients whose cancer failed to respond to initial treatment with immune checkpoint inhibitors.

Led by researchers at NYU Langone Health and its Perlmutter Cancer Center, the study focused on a subgroup of melanoma patients with mutations in the neurofibromin 1 (NF1) gene. NF1 mutations are just one type among several mutations, including those in the BRAF, NRAS, and PARP genes, that are linked to many cases of cancer, particularly melanoma. As many as 27% of melanoma patients are estimated to have NF1 mutations.

While immunotherapy, which stimulates the immune system to attack cancer cells as it would an invading virus, has proved to be a successful treatment, it does not work well for more than half of NF1-mutant melanoma patients.

“There is a pressing need for new drug therapies for melanoma patients with neurofibromin 1 mutations that do not respond to the latest immunotherapy, and for which there are no subsequent effective treatment options,” said study lead investigator Milad Ibrahim, PhD. Ibrahim is a postdoctoral fellow in the Dr Iman Osman Laboratory in the Ronald O. Perelman Department of Dermatology at the NYU Grossman School of Medicine.

To investigate why these patients were treatment resistant, investigators examined tumour cells from 30 melanoma patients who did not respond to immunotherapy. NF1 mutations were found in 40% of these melanoma samples. The samples came from NYU Langone’s extensive repository from more than 6000 melanoma patients.

Molecular testing showed that the signalling pathway built around a protein called epidermal growth factor receptor (EGFR) was more active in NF1 mutant melanoma cells than in cells with other melanoma-gene mutations. Increased EGFR activity has long been linked to abnormal cell growth in tumours and shorter survival with various cancers. The researchers also found that NF1 mutant melanoma cells depended on increased EGFR activity for survival, regardless of the presence of other mutations.

Because EGFR-inhibiting drugs are already used to treat some head and neck cancers, as well as colorectal and lung cancers, researchers then tested two drugs in the class, cetuximab and afatinib, in both NF1 mutant cell cultures and cancer cell lines without NF1 mutations. After transplanting both tumour cell types into mice and treating them with these drugs, results showed that both EGFR inhibitors were effective against cells and transplanted tumours with NF1 mutations, and they had no effect on melanomas without NF1 mutations.

“Our study results reveal a unique vulnerability in melanoma patients with neurofibromin 1 mutations, that an overexpression of the epidermal growth factor receptor pathway is essential for their survival and growth,” said the study’s senior investigator, Professor Iman Osman, MD.

“While further tests are needed, our results support a novel approach of deploying EGFR inhibitors either alone or in combination with other immunotherapies for treatment of melanoma patients whose tumours harbour NF1 mutation,” said the study’s co-senior investigator, Associate Professor Markus Schober, PhD.

However, Schober says this requires further testing in a clinical trial, which the research team plans to develop. He adds that if trial findings prove successful, the team’s research could provide a lifeline for many of these melanoma patients.

Source: NYU Langone Health

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Study Identifies Mitochondrial Drivers of Skin Cancer Aggressiveness – and Possible Treatments

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Mitochondrial pathways help melanoma cells become aggressive, and some currently available drugs target these pathways.

3D structure of a melanoma cell derived by ion abrasion scanning electron microscopy. Credit: Sriram Subramaniam/ National Cancer Institute

Researchers have discovered that the most aggressive melanomas, the deadliest form of skin cancer, overactivate two key processes in mitochondria. Blocking these pathways with currently available drugs effectively killed melanoma cells. The findings are published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society.

By mapping the proteins expressed in 151 tumour and normal skin samples, investigators found that the most aggressive melanomas hyper-activate the machinery that builds mitochondrial proteins and the mitochondrial system that turns nutrients into energy.

Remarkably, blocking these pathways effectively halted or killed melanoma cells cultured in lab dishes. Two types of drugs accomplished this: antibiotics, originally designed to block bacterial protein synthesis machinery, which closely resembles the machinery found in mitochondria, and specialised energy-production inhibitors. Importantly, non-cancerous skin cells remained mostly unaffected, highlighting the safety and specificity of these treatment approaches.

“This discovery identifies melanoma’s excessive reliance on mitochondrial energy as its Achilles’ heel, revealing a therapeutic vulnerability that we can exploit with existing drugs,” said senior author Jeovanis Gil, PhD, of Lund University in Sweden. “By pairing mitochondrial blockers with today’s standards of care, we may cut off a major escape route that cancers use to resist therapy and come back.”

Dr Gil added that the mitochondrial-protein signature his team discovered can be measured in routine biopsy material and could serve as a biomarker to identify patients most likely to benefit from mitochondrial-targeted add-on therapies. By enabling clinicians to match treatments to each patient’s tumour biology, these findings mark a step forward for precision medicine in melanoma. Moreover, because mitochondrial rewiring fuels resistance across many cancers, success in melanoma could open the door to similar personalised combination strategies in other hard-to-treat cancers. 

Source: Wiley

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How to Stop Melanoma’s Incredibly Swift Evasion of Treatment

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Melanoma Cells. Credit: National Cancer Institute

Researchers have uncovered a stealth survival strategy that melanoma cells use to evade targeted therapy, offering a promising new approach to improving treatment outcomes.

The study, published in Cell Systems and conducted by researchers at the Institute for Systems Biology (ISB) and Massachusetts Institute of Technology (MIT) identifies a non-genetic, reversible adaptation mechanism that allows melanoma cells to survive treatment with BRAF inhibitors. By identifying and blocking this early response, researchers proposed a combination therapy that could delay resistance and enhance the effectiveness of existing treatments.

Cracking the Code of Melanoma’s Drug Escape

Melanoma, the deadliest form of skin cancer, is often driven by mutations in the BRAF gene, which fuels uncontrolled tumor growth. While BRAF inhibitors (such as vemurafenib) initially halt tumor growth, many tumors quickly adapt and survive treatment, leading to therapy failure.

Unlike traditional resistance driven by genetic mutations, this study uncovers an early, dynamic adaptation process that occurs within hours to days of drug treatment – long before genetic resistance takes hold. Surprisingly, this process does not rely on reactivating the BRAF-ERK pathway, which is the usual resistance mechanism.

Using cutting-edge mass spectrometry-based phosphoproteomics and deep transcriptomics analyses, researchers mapped the molecular shifts in melanoma cells over minutes, hours, and days of BRAF inhibitor treatment.

“We found that while the BRAF-ERK signaling pathway was quickly and durably suppressed, cancer cells did not rely on reactivating ERK to survive. Instead, they triggered an alternative SRC family kinase (SFK) signaling pathway, which promoted cell survival and eventual recovery,” said Chunmei Liu, PhD, a bioinformatics scientist at ISB and co-first author of the paper.

Turning a Weakness Into a Target

A key discovery in this study came when researchers linked SFK activation to reactive oxygen species (ROS), a cellular stress response that builds up under BRAF inhibition. As ROS levels surged, SFK activity spiked, helping melanoma cells withstand treatment. However, this adaptation was reversible – when treatment was removed, cells returned to their original state.

Recognizing this Achilles’ heel, the team tested a combination approach: pairing BRAF inhibitors with the SFK inhibitor dasatinib.

“By adding dasatinib, we blocked this adaptive escape mechanism, significantly reducing melanoma cell survival and stabilising tumours in animal models,” said ISB Associate Professor Wei Wei, PhD, co-corresponding author.

Importantly, SFK inhibition alone had little effect on melanoma cells, highlighting the need for a strategic combination therapy to suppress melanoma adaptation before resistance fully develops. 

“This approach has the potential to prolong the effectiveness of BRAF inhibitors and improve patient outcomes,” said ISB President and Professor Jim Heath, PhD, co-corresponding author.

Looking Ahead: A Path to the Clinic

Beyond uncovering a key mechanism of drug adaptation, this research underscores the importance of early intervention to prevent it from happening. It also highlights ROS accumulation and SFK activation as potential biomarkers for identifying patients who may benefit from this combination therapy.

Further preclinical studies and clinical trials will be necessary to validate this combination therapy strategy and determine its potential for broader clinical use.

Source: Institute for Systems Biology

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New Combination Immunotherapy for Melanoma and Breast Cancer

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3D structure of a melanoma cell derived by ion abrasion scanning electron microscopy. Credit: Sriram Subramaniam/ National Cancer Institute

A research team at the Medical University of Vienna led by Maria Sibilia has investigated a new combination therapy against cancer. This therapy employs systemic administration of the tissue hormone interferon-I combined with local application of Imiquimod. Promising results were seen in topically accessible tumours like melanoma and breast cancer models: the therapy led to the death of tumour cells at the treated sites and simultaneously activated the adaptive immune system to fight even distant metastases. The findings, published in Nature Cancer, could improve the treatment of superficial tumours such as melanoma and breast cancer.

In recent years, immunotherapies have had significant success in the treatment and cure of a wide range of cancers. However, for some patients, these agents are still not sufficiently effective. As part of a preclinical study, Maria Sibilia, Head of the Center for Cancer Research at the Medical University of Vienna, therefore investigated the effects of a combination immunotherapy consisting of systemic administration of the tissue hormone interferon (IFN)-I and local imiquimod therapy. Imiquimod is an active substance that activates the innate receptors TLR7/8 and used to treat basal cell carcinomas. The researchers employed various preclinical mouse tumour models of melanoma and breast cancer. What both tumours have in common is that they are accessible to local therapy and often form distant metastases.

Effective for local tumours and distant metastases

Immunotherapies use the body’s own immune system to fight cancer cells. Plasmacytoid dendritic cells (pDCs), which are activated by Imiquimod via TLR7/8, play an important role in this process. The study showed that oral imiquimod stimulates pDCs to produce the tissue hormone IFN-I. This sensitised other dendritic cells and macrophages in the tumour environment to topical imiquimod therapy, which inhibited the formation of new blood vessels via the cytokine IL12 leading to the death of tumour cells.
The combination immunotherapy not only had an effect on the treated tumours, but also on distant metastases. It reduced the formation of new metastases thus preventing tumour relapses and increasing the sensitivity of melanomas to checkpoint inhibitors.

“These findings illustrate that the combination of systemic treatment with imiquimod or IFN-I and topical therapy with imiquimod has the potential to expand treatment options for patients and improve therapy outcomes in locally accessible tumors such as melanoma or breast cancer,” emphasizes Maria Sibilia.
“Topical treatment of the primary tumor with imiquimod is essential for this combination therapy with systemic IFN-I to be effective at the treated site and also to clear distant metastases,” adds Philipp Novoszel, MedUni Vienna, one of the first authors of the study.

The results suggest that this therapeutic strategy has the potential to improve treatment outcomes in superficial and thus locally accessible tumors such as melanoma and breast cancer – on the one hand through therapy-associated cancer cell death at the locally treated tumors, but also through the induction of a T cell-induced anti-tumor immune response at distant metastases, which is further enhanced by checkpoint inhibitors.

“Our aim is to continue developing immunotherapeutic strategies in order to improve the long-term prospects for patients who are not yet responding well to these agents,” says Maria Sibilia, who is also Deputy Head of the Comprehensive Cancer Center of MedUni Vienna and University Hospital Vienna.
“As systemic interferon is a well-known cancer therapy and dendritic cells are activated in a similar way to our preclinical models, we believe that the new combination therapy can show an effect in patients,” adds Martina Sanlorenzo, dermato-oncologist at MedUni Vienna and co-first author of the study.

Publication: Nature Cancer
Systemic IFN-I combined with topical TLR7/8 agonists promotes distant tumor-suppression by c-Jun-dependent IL-12 expression in dendritic cells
Sanlorenzo M, Novoszel P, Vujic I, Gastaldi T, Hammer M, Fari O, De Sa Fernandes C, Landau AD, Göcen-Oguz BV, Holcmann M, Monshi B, Rappersberger K, Agnes Csiszar A, Sibilia M
DOI: 10.1038/s43018-024-00889-9; https://www.nature.com/articles/s43018-024-00889-9

Source: Medical University of Vienna

Categories : CancerTags :

How, When and Where: Sex Matters in Melanoma Development

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Photo by Rfstudio on Pexels

Melanoma rates differ consistently between men and women in terms of the ages at which melanomas occur and the locations on the body where they occur. Over time, melanoma rates have increased in both men and women, but the trends differ by body site. A new study in the Journal of Investigative Dermatology, published by Elsevier, presents the findings from a large-scale, long-term melanoma data analysis investigating incidence trends by age, sex, and anatomic site.

Lead investigator David C. Whiteman, MBBS, PhD, Cancer Control Group, QIMR Berghofer Medical Research Institute, and Faculty of Medicine, The University of Queensland, Brisbane, Australia, explains, “There has been a general observation in numerous populations that melanomas appear to arise at different rates in men and women. We decided to investigate this observation rigorously and assess whether these differences have been constant through time or across generations by using large-scale data from population registries to investigate long-term melanoma trends in men and women.”

The research team analysed more than 40 years of melanoma data from Queensland, Australia, the USA, and Scotland. These three populations were chosen because historically they have had high (Queensland), moderate (USA), and low (Scotland) rates of melanoma. Over time, the rates of melanoma increased in all three populations, especially among women. In women in all populations, melanomas arise most commonly on the limbs, whereas in men, melanomas arise most commonly on the trunk and head and neck. In both sexes, there has been a steady increase in melanomas on the head and neck with increasing age.

Researchers found that in virtually all investigated populations, women experience higher rates of melanoma than men in early life (up to age ~45 years), but men develop melanomas at higher rates than women later in life (from ages ≥ 65 years). Furthermore, these sex-specific trends reflect complex patterns of incidence across body sites that vary consistently with age. Thus, in early life, women experience higher rates of lower limb melanomas than men, which persists into older ages. Also, on the upper limbs, women experience substantially higher rates than men from young ages until middle age (45–64 years), after which men experience higher rates. In contrast, on the head and neck and the trunk, melanomas occur at higher incidence in men than in women early in life. On all body sites, the rate at which melanoma incidence rises with age is much more rapid for men than for women.

The study confirms that men and women experience melanoma in different ways. While this is most likely driven by different patterns of sun exposure between men and women, there appear to be inherent differences in the ways in which melanomas develop at different body sites in women compared with men. Understanding the underlying biological differences could provide important clues about the etiology of this enigmatic cancer.

Source: Elsevier

Categories : Cardiovascular Disease Environmental EffectsTags :

Benefits of UV Exposure may Outweigh Risks in Low-sunlight Countries

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Photo by Julian Jagtenberg on Pexels

The health benefits of spending time in the sun could outweigh the risks for those living in areas with limited sunshine, a UK study suggests. In low-sunlight locations such as parts of the UK, exposure to higher levels of ultraviolet (UV) radiation was linked to a drop in deaths due to cardiovascular disease and cancer.

Adapting public health advice to reflect both the risks and benefits of UV exposure may help to reduce disease burden and improve life expectancy in low-sunlight countries, the research team says.

Experts caution that measures should still be taken to protect the skin when UV levels are high, to prevent sunburn and the development of skin cancer.

Volunteer data

University of Edinburgh scientists used genetic and health information from the UK BioBank – an anonymised database of health details from volunteers – to examine the UV exposure of 395 000 people across the UK. Participants were restricted to those of white European descent, due to the role skin pigmentation plays in the body’s response to UV exposure.

The team applied two measures to identify those exposed to higher levels of UV. They used the geographical location of participants to calculate their average annual exposure to solar energy and, separately, whether they used sunbeds.

The findings were adjusted for other factors that might influence health – including smoking, exercise, social deprivation and gender – to reduce the chance that these factors were responsible for any of the changes observed.

Health impact

Living in locations with higher UV levels, for example Cornwall, was associated with a lower risk of death from cardiovascular disease and cancer – 19% and 12%, respectively – than living in areas with lower UV levels, such as Edinburgh or Glasgow.

Sunbed use was linked to a 23% lower risk of death from cardiovascular disease and a 14% lower risk of death from cancer, compared to non-users. It is possible that people who use sunbeds may also seek out greater sun exposure and so this result may reflect broader sun seeking behaviour, the team says.

Those with a higher estimated UV exposure had a slightly increased risk of being diagnosed with melanoma, but their risk of dying from the condition was not raised.

As the study is based on UK data from a white European population, the findings are of most relevance to similar groups in low-sunlight countries. Further research into locations with higher UV exposure is needed to build a clearer picture of the potential benefits to health, experts say.

The study, funded by Health Data Research UK, is published in the journal Health and Place.

Our paper adds to a growing body of evidence suggesting that in lower light environments, relatively higher exposure to UV is good for your health. Though there may be an increased risk of skin cancer incidence with higher UV exposure, this risk appears to be outweighed by a larger reduction in the risk of death from cancer and cardiovascular related disease.

Professor Chris Dibben, University of Edinburgh’s School of GeoSciences

Dermatologists have traditionally only considered possible harm to the skin caused by sunlight, much of which dates from the experience of white-skinned individuals in sunny countries such as Australia. When the UV index is very high, protecting skin is important.

However, this research shows that in the UK, the balance of benefit and risk from sunlight exposure is probably very different from that in sunnier countries.

Professor Richard Weller, University of Edinburgh’s Centre for Inflammation Research

Source: The University of Edinburgh

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Unique Genetic Pattern can Predict Severe Side Effects of Melanoma Immunotherapy

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Melanoma Cells. Credit: National Cancer Institute

An activity pattern in certain genes responsible for building proteins known as spleen tyrosine kinases can predict which melanoma patients are likely to have severe side effects from immunotherapy designed to treat the most deadly skin cancer, as shown by a new study published in the journal Clinical Cancer Research.

Led by researchers at NYU Langone Health and its Perlmutter Cancer Center, the latest experiments focused on checkpoint inhibitors, drugs that have in the last decade become a mainstay of treating melanoma. This form of skin cancer kills nearly 10 000 Americans annually.

The drugs work by blocking molecules (checkpoints) that sit on the surface of immune T which the immune system uses to recognise and protect healthy cells. Cancer cells are able to hijack and turn off immune cell surveillance, evading detection. Immunotherapy drugs like nivolumab and ipilimumab are designed to block checkpoints, making cancer cells more “visible” again to T cells.

More than a third of melanoma patients given checkpoint inhibitors develop side effects so severe that they compromise their quality of life and ability to continue therapy. Side effects most often involve some form of inflammation, a sign of an overactive immune response. Patients may experience severe skin rashes, diarrhoea, or hyperthyroidism. More-severe side effects can include liver toxicity, colitis, and rheumatoid arthritis.

In the new study researchers found that even before treatment began in their test subjects, the activity of genes controlling the production of spleen tyrosine kinases predicted 83% of melanoma patients who eventually developed severe side effects from combined immunotherapy with nivolumab and ipilimumab.

Moreover, the researchers found that this heightened gene signature, as evidenced by the production of spleen tyrosine kinases, or the SYK pathway, did not interfere with the effectiveness of therapies in preventing recurrence of melanoma. The impact was connected only to side effects.

“Predictive information of this kind is critically important to oncologists and patients to help guide their immunotherapy decisions, to either minimize these side effects by taking additional precautions or to choose alternative immunotherapies,” said study co-senior investigator Tomas Kirchhoff, PhD.

“Our study results show that increased gene activity in the spleen tyrosine kinase pathway could be the basis of a possible blood test that identifies those melanoma patients most susceptible to having severe side effects from immunotherapy, and well before they start treatment,” said study co-lead investigator Kelsey Monson, PhD. 

For the study, researchers analysed immune system cell samples from 212 men and women with melanoma participating in the CheckMate-915 trial. The trial was designed to test whether combined therapy with nivolumab and ipilimumab worked better than single therapy with nivolumab in preventing postsurgical recurrence of melanoma. All immune cell samples were taken prior to the start of immunotherapy. Both drugs are manufactured by the pharmaceutical company Bristol Myers Squibb, which sponsored the CheckMate-915 trial, and provided the patient specimens and data used in the analysis.

When researchers looked at what genes were more active than others in patients who experienced side effects from their immunotherapy, they found a specific pattern among 24 genes tied to the production of spleen tyrosine kinases. Further statistical analyses showed that increased or decreased activity (transcription) of only five of these genes – CD22, PAG1, CD33, HNRNPU, and FCGR2C – along with patients’ age and the stage severity of their melanoma served as the best predictors of who would experience side effects from immunotherapy.

Study co-senior investigator Jeffrey S. Weber, MD, PhD, says that the SYK pathway has previously been linked to other autoimmune diseases, including lupus, rheumatoid arthritis, and colitis. He also points out that immunotherapy side effects were also most common in areas affected by these autoimmune diseases, including the skin, colon, and liver.

Dr Weber says the team next plans to investigate if an activated SYK pathway is predictive of side effects in patients treated with ipilimumab alone or with other combination immunotherapies.

“If our future research can explain how an activated spleen tyrosine kinase pathway leads to increased risk of side effects from immunotherapy, then it could also potentially help us to design better cancer immunotherapies and potentially other treatments for autoimmune diseases,” said Dr Kirchhoff.

Source: NYU Langone Health / NYU Grossman School of Medicine

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Malignant Melanoma Resists Treatment by Subverting Immune Cells

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3D structure of a melanoma cell derived by ion abrasion scanning electron microscopy. Credit: Sriram Subramaniam/ National Cancer Institute

Malignant melanoma is one of the most aggressive types of cancer. Despite recent progress in effective therapies, the tumours of many patients are either resistant from the outset or become so during the course of treatment.

A University of Zurich (UZH) study published in Cell Reports Medicine has now identified a mechanism involving subverted immune cells that impedes the effectiveness of therapies. The result provides new ideas for treatments to suppress the development of resistance.

Comparing resistant and non-resistant tumour cells

For the study, the team utilised an innovative fine-needle biopsy to sample tumour cells before and during therapy. This allowed the researchers to analyse each cell individually. The patients providing the samples were undergoing targeted cancer therapy for malignant melanoma, which inhibits signalling pathways for tumour formation.

“It was important that some of the tumours responded to the therapy, while others showed resistance,” says study leader Lukas Sommer, professor of stem cell biology at the Institute of Anatomy at UZH. This allowed the team to compare the metabolism and environment of resistant and non-resistant tumour cells and look for significant differences.

Interaction between tumour factor and immune cells

One of the most relevant findings concerned the POSTN gene: it codes for a secreted factor that plays an important role in resistant tumours. In fact, the tumours of patients with rapidly progressing disease despite treatment showed increased POSTN levels. In addition, the microenvironment of these tumours contained a larger number of a certain type of macrophage – a subtype of immune cell that promotes the development of cancer.

Through a series of further experiments – both with human cancer cells and with mice – the research team was able to show how the interaction of increased POSTN levels and this type of macrophage triggers resistance: the POSTN factor binds to receptors on the surface of the macrophages and polarises them to protect melanoma cells from cell death. “This is why the targeted therapy no longer works,” says Sommer.

No resistance without cancer-promoting macrophages

The team considers this mechanism a promising starting point. “The study highlights the potential of targeting specific types of macrophages within the tumour microenvironment to overcome resistance,” says Sommer. “In combination with already known therapies, this could significantly improve the success of treatment for patients with malignant melanoma.”

Source: University of Zurich