Published November 11, 2013
With the ultimate goal of designing new immunotherapeutic strategies, Richard B. Bankert, VMD, PhD, professor of microbiology and immunology, and his team are working to re-activate cancer-killing T cells in a tumor microenvironment.
To explore accomplishing this goal by blocking the activity of lipids that suppress a healthy immune response, Bankert has received a $1.66 million, five-year grant from the National Cancer Institute.
Bankert’s team has determined that fibroblasts in the tumor microenvironment produce these lipids — or soluble factors — that prevent the full activation of T cells.
The researchers believe that an arrest or checkpoint in the T cell receptor (TCR) signaling cascade contributes to the failure of these cells to control tumor growth, Bankert says.
They will now attempt to block or reverse the inhibition of the tumor-specific immune responses by identifying the inhibitory factors and determining their mechanisms of action.
Gaining insight into the molecular mechanisms that arrest the immune response is expected to lead to “novel methods to enhance the ability of a patient’s T cells to recognize and kill the tumor cells,” Bankert says.
The researchers initially plan to explore exactly how the tumor ascites fluid — or the two immunosuppressive polar lipids in them — arrest TCR signaling.
They plan to determine whether the fluid acts directly on T cells or whether an indirect process is involved whereby cells bind to (and are activated by) polar lipids.
Based on what they find out, they will attempt to either eliminate immunosuppressive lipids or functionally block lipid-binding cells.
The team also will assess whether their approach successfully prevents the arrest of TCR signaling — that is, do the T cells kill tumor cells?
To provide further insights into the molecular mechanisms of the lipid-induced TCR signaling arrest, the researchers will study the structure and function of the two polar lipids isolated from the tumor ascites fluid.
They will then work to target and block the specific molecular structures each molecule needs to inhibit immunity and allow cancer to progress.
The experiments require the use of a novel xenograft model Bankert designed that allows human tumors to be transplanted into immunodeficient mice.
“These mice represent patient avatars,” Bankert says.
The human tumors growing in them (the patient-derived xenograft) closely reflect the growth and therapy response observed in patients, he adds.
“They are extremely useful for testing the efficacy of novel therapeutic protocols and have the potential to predict patients’ responses to therapy.”
The model has made it possible, for the first time, to quantify and monitor intratumoral T cell function and to quantify changes in tumor cell numbers, Bankert says.
For more than 25 years, Bankert and his team have developed and used their xenograft model to study how tumor cells interact with other types of cells — including inflammatory leukocytes and fibroblasts — in human lung and ovarian tumor microenvironments.
The researchers are already taking steps to develop new immunotherapeutic strategies for patients with advanced cancer, Bankert says.
“We are collaborating with cancer clinicians and surgeons to translate our findings into treatments.”
The current project, “Re-activating Memory T Cells in the Microenvironment of Human Tumors,” involves a team of researchers with expertise in immunology, tumor cell biology, lipid biochemistry, genetics, animal modeling, membrane biophysics and clinical cancer immunotherapy.
Bankert’s collaborators include Raymond J. Kelleher, PhD, research associate professor of microbiology and immunology; Sathy Balu-Iyer, PhD, professor of pharmaceutical sciences; and scientists at Roswell Park Comprehensive Cancer Center, the Buffalo VA Medical Center and Jackson Labs, based in Bar Harbor, Maine.