Researchers have developed immunotherapy to slow progression of early-stage pancreatic tumors in mice. This approach might be developed to prevent progression of premalignant lesions to PDA, researchers report in the June issue of Gastroenterology.
Pancreatic ductal adenocarcinoma (PDA) is a difficult cancer to treat because it is usually detected at late stages, when it has become resistant to treatment. However, progression of PDA from its earliest, pre-cancerous lesions (known as pancreatic intraepithelial neoplasms or PanINs) to metastatic tumors is believed to take many years, providing a therapeutic window.
Bridget P. Keenan et al. developed an immunization strategy to target the early genetic changes that initiate premalignant lesion formation.
KrasG12D/+;Trp53R172H/+;Pdx-1-Cre (KPC) mice, which express an activated form of Kras (KrasG12D) in pancreatic tissues, develop PanINs that progress to PDA. These mice typically survive for only about 5 months.
Keenan et al. immunized these mice with Listeria monocytogenes engineered to express KrasG12D. The vaccine was given alone or in sequence with an antibody against CD25 and cyclophosphamide, to deplete T-regulatory (Treg) cells.
They found that in KPC mice 4–6 weeks old (with early-stage PanINs), the combination vaccine and Treg cell depletion prolonged survival almost 2-fold and reduced PanIN progression, compared with control mice.
Cancer progressed when KPC mice were given the engineered bacteria alone, even though this vaccine induced a significant peripheral CD8+ T-cell response against epitopes from the KrasG12D. Keenen et al. concluded that induction of systemic antigen-specific T cells is not sufficient for effective anti-tumor immunity–the Treg cell depletion was also required.
However, when the combination was administered to KPC mice 8–12-weeks old (with late-stage PanINs), it did not increase survival time or slow PanIN progression. The vaccine and Treg cell depletion appeared to stop progression of only early-stage pancreatic lesions.
How does this treatment combo work? Keenan et al. found that it reduced numbers of Foxp3+CD4+ T cells in pancreatic lymph nodes, and increased numbers of CD4+ T cells that secrete interleukin 17 and interferon-gamma. It also caused CD11b+Gr1+ cells in the pancreas to acquire an immunostimulatory phenotype.
The authors conclude that this approach increases infiltration of the lesions with inflammatory cells that alter the microenvironment and inhibit tumor progression.
Keenan et al. identified CD8+ and T-helper 17 cell populations as important effectors of PDA prevention.
Listeria-based vaccines have been previously shown to induce effective immune responses to tumor antigens. Keenan et al. say that effective pancreatic cancer vaccination strategies will also require inclusion of agents designed to alter the tumor’s inflammatory microenvironment.