Three studies reveal how tumors hijack the immune system to resist radiation therapy!

May 5, 2019 / BIOON / - more than ten years ago, radiation oncologists noticed an interesting phenomenon: sometimes local use of radiotherapy can stimulate the immune system, making the whole immune system attack cancer It's as if using radiation can somehow wake up the immune system to the presence of cancer Since then, efforts have been made to use this effect, hoping to create this systematic anti-cancer activity through the combination of radiation therapy and immunotherapy Unfortunately, "we've tried a lot of combinations with radiotherapy - triple therapy, different target strategies, etc - but we still can't cure tumors," said SANA Karam, MD, a researcher at the cancer center at Cambridge University and an assistant professor of radiation oncology at the school of medicine Photo source: http://cn.bing.com what causes the tumor to be resistant to radiotherapy? In a new study published in the Journal of the National Cancer Institute, Karam and colleagues said that this may be due to a special immune cell called T-regulatory cell or Treg cell Just as the body has the mechanism to turn on the immune system, it also has the method to turn off the immune system Treg is one of them Its function is like a "off" switch to prevent the immune system from running crazy in healthy tissues Treg is an immunosuppressive cell that inhibits effector T cells But Treg also prevents T cells from killing cancer cells In this study, Karam, together with the first author, Dr Ayman oweida, found that radiation alone or Treg depletion was not enough to kill head and neck cancer in mice, but the combination of the two strategies could effectively reduce the tumor This strategy makes sense: radiation turns on the immune system, and Treg's consumption ensures that cancer cannot shut it down "If you do this just by removing Treg, there's no effect on T cells You need something to stimulate the immune system, something to activate T-effector cells, and in our study, radiation plays that role Unfortunately, we don't have a good, safe drug to safely remove Tregs from humans We do this as a good way to understand biology, but it's not a good strategy for patients, "Karam said Photo source: http://cn.bing.com this is the second part of the research Karam is also working on a study of early embryonic development Specifically, the "handshake" between EphB4 and EphrinB2 is crucial for neurogenesis in the developing brain, but previous studies have shown that the levels of EphB4 and / or EphrinB2 have increased in many cancers, including head and neck and pancreatic cancer "EphB4 has been studied not only for cancer, but also for many diseases where the immune system plays a key role In cancer, we have shown that when you inhibit the interaction between EphB4 and EphrinB2, your tumor growth decreases We are conducting a trial at the Cu cancer center using a drug to inhibit the interaction between ephb4-ephrinb2 But we also want to know why inhibiting this interaction works on tumors, "Karam said The team recently published a paper in the journal Cancer Research with the first author, Dr Shilpa Bhatia, showing that the most significant result of inhibiting this communication between EphB4 and EphrinB2 is the reduction of T-regulatory cells "It's a complete coincidence," Karam said "In this study, we really didn't plan to study Treg Many studies have focused on activating T-effector cells But we found in our model that when we supported the interaction of EphB4 EphrinB2, we did not see more T-effector cells, but suddenly cleared the Treg inhibitory cells to make T-effector cells more active and play a role " "Both studies were conducted at the same time, and we happened to find common ground on Tregs," Karam said That's the beauty of science You never know what you're going to get " In a third study, published jointly with the first author Shelby Lennon in the Journal of clinical cancer research, the team tested the inhibition of EphrinB2 in a pancreatic cancer model For a long time, researchers have known that the expression of EphrinB2 in pancreatic cancer is related to poor prognosis In collaboration with several partners, the researchers found that inhibition of EphrinB2 can lead to lower degree of fibrosis in these tumors, which means that the density of the tumor wrapped by cross-linked collagen fibers is lower Previous studies have shown that the permeability of anticancer drugs in pancreatic tumors is poor, and pancreatic adenocarcinoma is less affected by the immune system, and it is easier to metastasize Source: http://cn.bing.com Karam said: "we see a significant reduction in fibrosis and a significant reduction in disease burden." Usually, new anticancer drugs are tested "from the bottom up" or "from the top down": either many drugs are tested with cells in order to find specific weaknesses; or, scientists have found a specific weakness and designed a drug to use it So far, two studies on Treg seem to come from two directions First, in a top-down approach, the presence of Tregs seems to help cancer resist radiation; second, in a bottom-up approach, it seems that inhibition of the EphB4 EphrinB2 axis can inhibit these Tregs "Only when you really understand the basic biological principles, understand the mechanism of things, can you develop a reasonable treatment against cancer," Karam said Now, with the development of radiotherapy resistance to Treg and the reduction of EphB4 EphrinB2 that can reduce Treg awareness, the team can continue to develop safe and effective drugs to target this cancer growth and resistance mechanism Reference materials: [1] three students show how tutorials hijack the immune system to resist radiation therapy [2] Ayman J oweida et al, the role of regulatory T cells in the response to radiation therapy in head and neck cancer, JNCI: Journal of the National Cancer Institute (2019) DOI: 10.1093/jnci/djz036 【3】Shilpa Bhatia et al Inhibition of EphB4-ephrin-B2 signaling reprograms the tumor immune microenvironment in head and neck cancers .Cancer Research DOI: 10.1158/0008-5472.CAN-18-3257 【4】Shelby Lennon et al Pancreatic Tumor Microenvironment Modulation by EphB4-ephrinB2 Inhibition and Radiation Combination Clinical Cancer Research DOI: 10.1158/1078-0432.CCR-18-2811