Dr. Ned Waller explained how a neuropeptide first studied in the gut emerged as a potential immune checkpoint affecting T cells, macrophages and cancer cells.
Pancreatic cancer has proved especially difficult to treat with immunotherapy. A major barrier is the immunosuppressive environment the tumor creates around itself, including dense stroma that can limit immune-cell access and signals that suppress immune activity within the tumor.
What this means, simply, is that the tumor can keep immune cells out and suppress those that make it inside.
Researchers are now studying whether vasoactive intestinal peptide (VIP), a signaling molecule, helps create these immune-suppressing conditions and whether blocking VIP signaling could make some cancers easier for the immune system to attack.
In an exclusive interview with Xtalks, Dr. Edmund (Ned) Waller, MD, PhD, Founder of Cambium Oncology, discussed how his team came to view VIP as a different type of immune checkpoint, how the pathway can influence several components of the tumor microenvironment and why researchers are studying it in cancers as different as pancreatic cancer and leukemia.
Professor of Hematology and
Medical Oncology, Emory University
Founder of Cambium Oncology
Dr. Waller also outlined what would need to be demonstrated in human cancers before the findings could move closer to clinical use.
From Pig Intestines to Cancer Checkpoints
VIP does not fit the traditional model of an immune checkpoint.
“VIP is known as a neuropeptide. It was originally isolated from the intestines of pigs and is responsible for some of the peristalsis of the intestine, but it also has a very important function as a regulator of immune response,” Dr. Waller said.
The pathway’s connection to cancer immunity emerged after Dr. Waller and colleagues observed that mice genetically lacking VIP were resistant to transplantable leukemia cell lines and viral infection. Pharmacologically blocking the VIP receptor produced some of the same effects, providing evidence that the response was linked to VIP signaling.
Subsequent work showed that some cancers, including pancreatic cancer and acute myeloid leukemia (AML), can overproduce VIP and that signaling through the pathway can restrain T-cell activation and anti-tumor immunity in experimental models.
“That led us to think of VIP and its receptors as a different type of immune checkpoint, one mediated by a soluble neuroimmune peptide rather than the cell surface interactions targeted by most of the current immune checkpoints such as PD-1 and the ligand PD-L1,” Dr. Waller said.
Programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) work through interactions at the cell surface. VIP gives researchers another way to examine how tumors may suppress immune activity.
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VIP Signaling Across the Tumor Microenvironment
Preclinical studies suggest that VIP signaling can influence several parts of the immune response.
In T cells, the pathway can limit activation, proliferation and effector function. In macrophages, VIP signaling appears to promote an immunosuppressive, tumor-supporting state that can interfere with their ability to engulf tumor cells and present antigens to T cells.
There is also evidence that VIP receptor signaling can act directly on some cancer cells and influence pathways associated with tumor progression, metastasis and immune suppression.
“So by blocking this pathway, we can then reshape many components of the immune system simultaneously rather than acting simply on a single immune cell population,” Dr. Waller explained.
— Edmund K. Waller, MD, PhD, FACP, Professor of Hematology and Medical Oncology, Emory University; Founder of Cambium Oncology
A Shared Mechanism Across Different Cancers?
Pancreatic cancer and AML can both create immune environments that help malignant cells escape immune attack.
Hypoxia, or low oxygen levels in tissue, is an important feature of both pancreatic cancer and leukemia microenvironments. “We’ve found that hypoxia can increase VIP production by cancer cells, potentially creating a feedback mechanism whereby the stress cancer cell creates the conditions that make the tumor even more immunosuppressive,” Dr. Waller said.
This could create a reinforcing cycle, in which low oxygen increases VIP production, while VIP signaling may further suppress anti-tumor immunity.
What Will It Take to Translate the Biology?
An interesting biological association is not enough in and of itself to establish a therapeutic target.
“I’m a clinician and a translational scientist, and for me, a pathway becomes compelling when there’s evidence for causality for a therapeutic target rather than simply coincident association,” Dr. Waller said.
This involves establishing whether the biology observed in experimental models also occurs in human cancer.
His team is studying human pancreatic tissue and experimental systems that recreate interactions between human T cells and leukemia cells. The researchers plan to use high-dimensional RNA sequencing to examine how blocking the VIP receptor changes T-cell activation and differentiation and affects monocytes and other immune cells.
They also want to determine whether those immune changes correlate with anti-tumor activity and identify biomarkers that could indicate which tumors and patients are most dependent on VIP signaling.
Three questions now guide that work: which cancers and patients depend on VIP-mediated immune suppression, which immune and tumor cells are the key targets of the pathway in humans and whether VIP blockade can be combined with chemotherapy, targeted therapies and established immune checkpoint treatments.
“Answering these three questions will determine whether this biology can ultimately be translated into a new and hopefully useful approach to cancer treatment,” Dr. Waller said.
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