Evolution of Stromal Niches in Inflammation, Cancer and Immunotherapy
Shannon Turley, Ph.D., Vice President of cancer immunology discovery at Genentech
Antibody sector should examine the role stromal cells play in disease
Connective tissues can make medicines less effective, according to a leading researcher, who says the antibody sector should consider them as a potential target for therapies.
Stromal cells are the connective tissue cells that build the infrastructure of organs. They also play a significant role in disease and response to medicines, according to Shannon Turley, Ph.D., Vice President of cancer immunology discovery at Roche-owned biotech company, Genentech.
“Stromal cells are very relevant to non-response and drug resistance and different kinds of diseases,” she told delegates at the Antibody Engineering and Therapeutics US 2023 conference.
“And I think we have a lot to do yet to be able to effectively target these cells. I’m hoping some of you folks can help us figure out how to do that.”
Fibroblasts
As an example, Turley cited fibroblasts: fibrous cells that support and connect tissues or organs.
“We know these cells play really important roles in establishing tissues and promoting tissue homeostasis. But they’re also really important in promoting disease.
“And more, we understand that their function in disease tissues can underlie, lack of response and poor responses to different therapies, particularly immunotherapy but also chemotherapies,” she said.
Turley proposed stromal cells as therapeutic targets, suggesting drugs that block their pro-disease function while keeping intact the stromal elements that are necessary would benefit patients.
Again she used fibroblasts as an example, explaining that while “they do promote wound healing, sometimes wound healing that goes too far and can lead to fibrosis.
“These cells promote tumor growth in some tissues and also metastasis,” she said, adding “They’re key contributors making enormous amounts of cytokines and chemokines … so promoting inflammation under certain circumstances.”
Fibroblasts also play a role in the range of responses seen to anti-tumor necrosis factor (TNF) drugs in some autoimmune and inflammatory diseases, according to Turley.
“For example, in inflammatory bowel disease, a lot of the patients that don’t respond well to anti-TNF have strong signatures of inflammatory fibroblasts. And somehow those cells seem to be communicating with inflammatory myeloid cells.”
But knowing stromal cells play a role in disease is only part of the battle, according to Turley.
“What to do about it, we have not figured out yet,” she said.
“We firmly believe that developing therapeutics to modulate the stromal is going to be important to bring more benefit to more patients, but we don’t understand the compartments well enough yet.”
Research focus
To address this, Turley and colleagues at Genentech are trying to gain a more precise understanding of how stromal cells function in both diseased and healthy tissues.
“As an example, in the fibrotic lung, we know fibroblasts, which become myo-fibroblasts, are the main driver of the later stages of this disease, depositing massive amounts of extracellular matrix and also promoting cross-linking of this matrix such that the tissue becomes heavily stiffened and can no longer function properly,” she said.
“So we need to know, what are the communities in which the fibroblasts are functioning? What other cells are they interacting with? Specifically, where are those cellular neighborhoods, and how are they contributing to disease or to resolution of disease?”
Antibody sector
Answering these questions will prompt the development of therapies, according to Turley, who urged the antibody sector to look more closely at how stromal cells function in disease.
“We do think that stromal cells promote disease and therapeutic resistance in many inflammatory diseases. But there are not very many options for dealing with this compartment and that is probably because we just haven’t really understood how they work, how they develop, and how to get at them.
“I think in order to get at them, we’re going to have to spend a little bit more time studying them. But I think the field is really moving quickly and there are many options for those of you making antibodies,” she said.
Turley suggested developers need to identify markers on stromal cells “so we can begin manipulating them better with antibodies and other approaches.”
