A new discovery about cancer and the immune system points to previously unrecognized targets for drug development to battle solid tumors.
The research also suggests that a drug already in use for more than a decade to treat non-Hodgkin’s lymphoma might also be useful in treating some solid tumors.
This strategy is unusual in that it would employ drugs that target cells or functions of the immune system to fight solid tumors, rather than cancers that arise in cells of the immune system.
A research team led by Lisa Coussens, PhD, a professor of pathology at UCSF and a pioneer in studies of inflammation and cancer, has found a cancer-promoting role for a specific molecule of the immune system. The study appears online in the scientific journal Cancer Cell. Already Coussens is collaborating with pharmaceutical industry scientists to explore therapeutic strategies arising from this molecular discovery.
Biochemical and cellular studies over the past decade have shown that inflammation can promote the development of cancer. In addition, certain chronic inflammatory conditions, such as Crohn’s disease, pancreatitis, prostatitis, asbestosis and Barrett’s esophagus, are associated with an elevated cancer risk.
Coussens, a member of the UCSF Helen Diller Family Comprehensive Cancer Center, has explored chronic inflammation in cancer caused by cells guiding the two different kinds of immune response – T cells and B cells of the adaptive immune system, as well as myeloid cells of the innate immune system, which typically regulate more general immune responses at sites of infection or injury.
Cells of the immune system may sometimes activate immune responses that inhibit the development of cancer, but in many pre-cancerous cellular milieus, the immune system can be driven into an ongoing inflammatory state that actually helps abnormally growing cells to develop into potentially deadly cancers.
Inflammation and Cancer
In general, the past decade’s research has made it clear that, “Chronic inflammation in the context of tumor development is associated with a poor prognosis,” Coussens says.
Coussens has found that both types of immunity contribute to an inflammatory environment that can promote the development of cancer. In 2005, her lab group reported that B cells in particular are essential for the cancer-promoting effect in squamous cancers, a type of skin cancer. B cells are best known for making antibodies that target specific infectious disease agents. But antibodies can play other roles in guiding immune responses.
Now Coussens and her lab group have identified a biochemical mechanism that links certain actions of B cells to the growth of cancer. The key appears to be the familiar class of antibodies known as immunoglobulin G (IgG) and receptors to which these antibodies attach on cells of the immune system.
The receptors that promote solid tumor growth when activated by IgG antibodies, known as Fc gamma receptors (FcRg), are found on mast cells, macrophages and other cells of the innate immune system. The activation of FcRg plays a role in recruiting mast cells and other immune cells to neoplastic tissue, which in turn enhances progression to cancer and development of new blood vessels to feed nutrients to growing tumors.
Coussens’ lab team, in experiments performed by postdoctoral fellows Pauline Andreu, PhD, Magnus Johansson, PhD, and Nesrine Affara, PhD, found that mice genetically predisposed to develop squamous cancers were much less likely to develop cancer when they also lacked FcRg receptors, or when they lacked IgG-producing B cells.
“The notion that immunoglobulins may enhance the development of some cancers has not been previously considered,” Coussens says. “We know that cancer patients have higher IgG levels, and this new research says that in some cases, this might be promoting tumor development, or at least tempering the effects of some cytotoxic therapies.”
Most tumors are rife with activated immune cells, Coussens says. “Their cancer-promoting roles have been largely overlooked, as have studies to investigate possible tumor-promoting roles for some immunoglobulins as regulators of solid-tumor development. These discoveries open up many new signaling molecules to think about as potential therapeutic targets.”
In their Cancer Cell report the researchers write, “These findings have broad clinical implications, as they reveal critical signaling pathways regulated by humoral immunity and FcRg to target therapeutically in patients at risk for cancer , e.g., patients suffering from chronic inflammatory diseases, as well as individuals harboring premalignant lesions where chronic inflammation compromises tissue integrity and enhances risk of malignancy.”
Greater success in treating certain solid tumors might result from combining chemotherapy with drugs that can thwart cancer-promoting activities of the immune system, Coussens says. For example, Rituxan is a drug with relatively few side effects that is used to treat cancers of B cells, such as non-Hodgkin’s lymphoma.
In mice genetically engineered to model squamous cancers, Coussens and collaborators from Genentech now are conducting combinatorial trials with Rituxan and chemotherapy, she says, and “finding exciting results that look promising.”
“It is paradigm shifting,” she adds. “We believe there are going to be solid tumors for which patients will benefit from Rituxan therapy.”
FcR Activation Regulates Inflammation-Associated Squamous Carcinogenesis
Pauline Andreu, Magnus Johansson, Nesrine I. Affara, Ferdinando Pucci, Tingting Tan, Simon Junankar, Lidiya Korets, Julia Lam, David Tawfik, David G. DeNardo, Luigi Naldini, Karin E. de Visser, Michele De Palma, Lisa M. Coussens
Cancer Cell (Published Online February 4, 2010)
Humoral Immunity, Inflammation and Cancer
Current Opinion in Immunology, April 2007