B cells are thought to play a critical role in innate and adaptive immunity, but their exact role in anti-tumour immunity remains unknown. Looking at B cells with a technique called single-cell profiling, which looks at all the genes in the cell, researchers found a protein that – when deleted – reduced tumour growth. The researchers write in Nature that this regulator could be a target for new cancer treatments.
The team, consisting of immunologists at Brigham and Women’s Hospital and dermatologists from Massachusetts General Hospital, identified a subset of B cells that expands specifically in the draining lymph node over time in mice with melanoma tumours.
They found a cell surface receptor called TIM-1 expressed on these B cells during melanoma growth. They also characterised multiple accompanying cell surface proteins that were involved in the B cell’s immune function. Interestingly, they found that deleting a molecule TIM-1, but not any of the other accompanying proteins, dramatically decreased tumour growth. The researchers concluded that TIM-1 controls B cell activation and immune response that combats cancer, including activating another type of the killer tumour-specific T cells for inhibiting tumour growth.
“The collaboration across institutions was extremely fruitful as we combined our immunology expertise at the Brigham with work at David Fisher’s MGH laboratory where seminal discoveries in skin malignancies have been made,” said lead author Lloyd Bod, PhD, of the Department of Neurology at the Brigham, who conducted this work while completing his postdoctoral fellowship at the Brigham. “The collaboration allowed us to test and demonstrate the therapeutic potential of targeting TIM-1 in melanoma models.”
Melanoma cells. Source: National Cancer Institute.
A review of data, published in Annals of Surgical Oncology, shows that completion lymph node dissection surgery for patients with stage III melanoma confers no benefit. This is especially true given that immunotherapy has shown success in treating metastases.
For years, surgery for patients with stage III melanoma, where the cancer had metastasised into lymph nodes, involved removing them along with the primary tumour. Known as completion lymph node dissection (CLND), the surgery was meant to ensure that no cancer remained after surgery.
More recently, however, cancer surgeons have discovered that CLND has the potential to cause more problems than it solves. In most cases, patients do better on immunotherapy alone than they do when their surgery involves removal of the lymph nodes, due to potential complications from lymph node surgery.
To address this, researchers reviewed their patient data to determine if immunotherapy alone resulted in better outcomes than CLND.
“In the few years prior to immunotherapy being available, some surgical trials were done asking if regional node dissection by itself improves overall survival for the patients,” said Martin McCarter, MD, a professor of surgical oncology at the University of Colorado (CU). “And the answer came back: no, it did not improve survival. That had been the standard forever, because we didn’t have other effective therapies, but once the definitive trials were done, we learned that CLND wasn’t helping, it wasn’t improving survival. Subsequent trials demonstrated that immunotherapy can improve survival in metastatic melanoma.”
For the study, the researchers looked at data on 90 patients who underwent sentinel lymph node biopsy (a procedure to determine if a skin melanoma has spread microscopically) only for stage III melanoma but did not undergo CLND. Of those patients, 56 received immunotherapy and 34 did not. Those who received immunotherapy had better rates of distant metastasis-free survival, meaning their cancer was less likely to come back.
“As treatments for melanoma have evolved, the standard of care may be evolving as well,” Prof McCarter said. “This study took a look at the patients who had a sentinel lymph node biopsy, so we knew the patient had a positive melanoma metastasis to their regional node. Those folks historically used to go on and get the completion lymph node dissection, but recently, people started to forego doing that lymph node dissection, which did not improve survival, and instead moved directly to immunotherapy, which did improve survival in other clinical trials. We proved that this is acceptable, that we’re not causing more harm to patients by doing it, and that those who do go on to get the immunotherapy seem to benefit from it.”
Forgoing CLND is part of a recent movement in cancer treatment known as de-escalation (or de-implementation) — performing only absolutely needed surgery. It’s especially important when it comes to lymph node surgery, Prof McCarter said, as in addition to the usual surgical risks, CLND has a 20% to 30% risk of permanent lymphoedema.
“If you could avoid that complication and not compromise a patient’s survival, that would be beneficial,” McCarter said. “That’s what we guessed was happening outside of definitive clinical trial evidence, and that’s what we were able to show. We know that we often overtreat patients, and this fits in that paradigm of finding ways to de-escalate unnecessary therapies, which has been done in breast cancer and other cancers as well.”
The researchers hope the findings will sway surgeons for whom CLND is still routine, despite the earlier studies showing that the additional surgery was not improving survival.
“Previous clinical trials with the use of adjuvant immunotherapy for melanoma had required a CLND,” Prof McCarter explained. “This study used real-world data from our stage III melanoma patients who were treated with immunotherapy without having a prior CLND.
“It takes years to change people’s practice patterns. I still have conversations with community surgeons who treat melanoma, asking me, ‘Should I be doing these regional node dissections?’ even though this data has been out for five to 10 years now,” Prof McCarter continued. “They’re afraid to give up what they used to do, and they’re afraid that they are doing a disservice to the patients or not giving them the best chance, when in reality, our understanding of cancer biology has evolved. We now have effective immunotherapy, which is overcoming some of the limitations of surgery while improving outcomes.”
Melanoma cells. Source: National Cancer Institute.
Moles and melanomas are both skin tumours that come from melanocytes. Moles are usually harmless, while melanomas are cancerous and often deadly without treatment. A study published in eLife Magazineexplains how common moles and melanomas form and why sometimes moles turn into melanoma.
Melanocytes produce melanin that protects the skin against UV radiation. Specific changes to the DNA sequence of melanocytes, called BRAF gene mutations, are found in over 75% of moles. The same change is also found in 50% of melanomas and is common in lung, colon and other cancers. It was thought that when melanocytes only have the BRAFV600E mutation the cell stops dividing, resulting in a mole. When melanocytes have other mutations with BRAFV600E, they divide uncontrollably, turning into melanoma. This model is called ‘oncogene-induced senescence’.
“A number of studies have challenged this model in recent years,” said Robert Judson-Torres, PhD, Huntsman Cancer Institute (HCI) researcher and University of Utah (U of U) assistant professor. “These studies have provided excellent data to suggest that the oncogene-induced senescence model does not explain mole formation but what they have all lacked is an alternative explanation – which has remained elusive.”
The study team took moles and melanomas donated by patients and used transcriptomic profiling and digital holographic cytometry. Transcriptomic profiling lets researchers determine molecular differences between moles and melanomas. Digital holographic cytometry helps researchers track changes in human cells.
“We discovered a new molecular mechanism that explains how moles form, how melanomas form, and why moles sometimes become melanomas,” said Prof Judson-Torres.
The study shows that additional mutations for melanocytes to turn into melanoma are not needed, but environmental signalling can be a trigger for the cells. Melanocytes express genes in different environments, instructing them to either divide uncontrollably or stop dividing altogether.
“Origins of melanoma being dependent on environmental signals gives a new outlook in prevention and treatment,” said Prof Judson-Torres. “It also plays a role in trying to combat melanoma by preventing and targeting genetic mutations. We might also be able to combat melanoma by changing the environment.”
These findings create a foundation for researching potential melanoma biomarkers, allowing doctors to spot cancerous changes in the blood sooner. The researchers are also keen to use these data to better understand potential topical agents to reduce risk melanoma risk, delay development, or stop recurrence, and to detect melanoma early.
Researchers may have hit upon a new weapon in the fight against melanoma: antibiotics that target a vulnerability in the ‘power plants’ of cancer cells when they try to survive cancer therapy.
“As the cancer evolves, some melanoma cells may escape the treatment and stop proliferating to ‘hide’ from the immune system. These are the cells that have the potential to form a new tumor mass at a later stage,” explains cancer researcher and RNA biologist Eleonora Leucci at KU Leuven, Belgium. “In order to survive the cancer treatment however, those inactive cells need to keep their ‘power plants’—the mitochondria—switched on at all times.” As mitochondria derive from bacteria that, over time, started living inside cells, they are very vulnerable to a specific class of antibiotics. This is what gave us the idea to use these antibiotics as anti-melanoma agents.”
The researchers implanted patient-derived tumors into mice, which were then treated with antibiotics, either as alone or in combined with existing anti-melanoma therapies. Leucci observed: “The antibiotics quickly killed many cancer cells and could thus be used to buy the precious time needed for immunotherapy to kick in. In tumors that were no longer responding to targeted therapies, the antibiotics extended the lifespan of—and in some cases even cured—the mice.”
The researchers made use of nearly antibiotics rendered nearly obsolete because of antibiotic resistance. However, this does not affect the efficacy of the treatment in this study, Leucci explained. “The cancer cells show high sensitivity to these antibiotics, so we can now look to repurpose them to treat cancer instead of bacterial infections.”
However, patients with melanoma should not try to experiment, warned Leucci. “Our findings are based on research in mice, so we don’t know how effective this treatment is in human beings. Our study mentions only one human case where a melanoma patient received antibiotics to treat a bacterial infection, and this re-sensitized a resistant melanoma lesion to standard therapy. This result is cause for optimism, but we need more research and clinical studies to examine the use of antibiotics to treat cancer patients. Together with oncologist Oliver Bechter (KU Leuven/UZ Leuven), who is a co-author of this study, we are currently exploring our options.”
Journal information: Roberto Vendramin et al, Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma, Journal of Experimental Medicine (2021). DOI: 10.1084/jem.20210571
A study reports that melanoma mortality among people in Utah, a sunny, high-altitude state, outpaced that of the rest of the country over 1975 to 2013.
This runs counter to the falling melanoma death rates in recent years in both Utah and the United States, a trend likely due to improved treatments such as immunotherapy. It is still the deadliest skin cancer type, with melanoma diagnosis rate in Utah the highest in the US.
Motivation for the research was recent evidence showing that for most of the 1990s and 2000s, even as melanoma mortality in the United States remained constant, incidence increased six-fold. This increasing incidence without accompanying mortality rise indicates overdiagnosis, ie false cancer diagnoses.
In the case of melanoma, overdiagnosis may result from increased scrutiny, where increasing numbers of biopsies may find a benign lesion that would have gone undetected.
Since Utah has the highest melanoma incidence, a team from Huntsman Cancer Institute (HCI) at the University of Utah set out to evaluate the state’s melanoma diagnosis and death rate data. Biostatistician Kim Herget analysed data from the Utah Cancer Registry, a National Cancer Institute Survival, Epidemiology, and End Results (SEER) database, and the researchers found that in contrast to the rest of the country, melanoma mortality in Utah rose 0.8% per year from 1975 to 2013. Even though Utah’s melanoma death rates have been falling in recent years, they are still higher than the rest of the country.
“Although we agree that overdiagnosis of melanoma is a growing problem, the sustained increase in melanoma mortality in Utah suggests that at least some fraction of the increasing incidence is real and cannot be attributed solely to overdiagnosis,” said Doug Grossman, MD, PhD, who co-leads the HCI melanoma and skin cancer centre at HCI and serves as professor of dermatology at the University of Utah. “Our research underscores an increased risk for Utahns, and so we must remain vigilant about melanoma. For doctors, this means regular conversations with patients about their skin health and family history. For patients, this means practicing sun-safe behaviors like diligent sunscreen use, wearing sun-protective clothing, and monitoring their skin at home on a monthly basis to reduce risk of skin cancer and optimize early detection.”
Future studies should determine whether this trend in people living in Utah results from increased ultraviolet exposure in a mostly fair-skinned population living in a sunny, high-altitude climate or if it is associated with other factors such as environment or genetics. Melanomas are also found at higher rates in immune compromised patients.
