University of Pittsburgh School of Medicine and UPMC Hillman Cancer Center scientists have discovered a novel subset of cancer-fighting immune cells that reside outside of their normal neighborhood – known as the tertiary lymphoid structure – where they become frustratingly dysfunctional when in close contact with tumors.
Described today in the journal Science Translational Medicine, the finding gives oncologists a new target for developing immunotherapies: double negative memory B cells, so-called because they are negative for two markers found on the surface of their more common brethren. They may also be a useful diagnostic marker when creating treatment plans.
“The responsiveness of B cells is an important part of whether a patient with cancer does well or not,” said senior author Tullia Bruno, Ph.D., assistant professor of immunology at Pitt and a member of the Cancer Immunology and Immunotherapy Program and Tumor Microenvironment Center at UPMC Hillman. “By better understanding different types of B cells and their location, we can aim to reinvigorate them and unleash their anti-tumor potential.”
B cells are white blood cells, produced in the bone marrow, that neutralize pathogens – such as bacteria, viruses and cancer cells – and tag them for removal from the body. Memory B cells are particularly long-lived and “remember” pathogens, priming the immune system to respond quickly if it encounters the pathogen again. When someone has cancer or a chronic infection, their body may form tertiary lymphoid structures near or within the cancer. The structures contain immune cells – predominantly B cells – and patients with the structures tend to have better outcomes.
While doing her graduate work in Pitt’s Program in Microbiology and Immunology, co-lead author Ayana Ruffin, Ph.D., now a postdoctoral research fellow at Emory University, observed that memory B cells were abundant in the blood of head and neck cancer patients – particularly those doing well. Curious, she pored over existing research and found that, while double negative memory B cells were well-characterized in chronic infection and autoimmune studies, little was known about their role in cancer.
She turned from blood to tumor samples and found double negative memory B cells there as well – but they were more dysfunctional, displaying features of exhaustion. Exhaustion is something cancer immunologists have been focused on with T cells – immune cells that destroy pathogens, such as cancer. But Ruffin was one of the first to observe this exhaustion in memory B cells in and near tumors, outside of the tertiary lymphoid structure.
“Historically, B cells have largely been ignored in the cancer research field, with scientists instead favoring research on ‘killer’ T cells,” said co-lead author Allison Casey, Ph.D. candidate in Pitt’s Molecular Genetics and Developmental Biology graduate program who took over the research when Ruffin graduated. “But B cells are really unique – they’re like the cool person at school who talks to everyone. They can use antibodies to neutralize pathogens and engage other immune cells. They educate T cells so they know to destroy cancer or infections.”
Casey and the research team are now exploring existing cancer immunotherapies – which are mostly aimed at helping T cells fight cancer – to see if there are ways to modify them to also boost memory B cells. They’re also investigating B cell therapies used in autoimmune diseases to see if they can be leveraged to fight cancer.
“This is a really good example of when a graduate student comes to you with an awesome idea and runs with it – she breaks new ground in the field,” Bruno said. “This research is a testament to what happens when students are encouraged to think creatively.”
