NEW YORK (GenomeWeb) – New research suggests that an immune checkpoint protein called VISTA may serve as a target for future immunotherapy development in pancreatic ductal adenocarcinoma (PDAC), which is known for its poor outcomes and resistance to existing immune checkpoint therapies that target proteins such as PD-1 or CTLA4.
Researchers from the MD Anderson Cancer Center and elsewhere used Nanostring analyses, immunohistochemistry staining, and other approaches to profile immune cell infiltration and expression features in dozens of untreated primary or treated metastatic PDAC cases, comparing the microenvironment features to those found in 44 cases of untreated, metastatic melanoma — a tumor type that is far more apt to respond to available checkpoint blockade immunotherapies.
In the process, the team uncovered distinct relationships between tumor and microenvironment cells in the two cancer types, including VISTA-expressing immune cells that appeared to mark PDAC cases with poorer outcomes.
"Our study highlights VISTA-positive macrophages as one of the potential inhibitory cell types that may affect pancreatic cancer patients' clinical outcomes," the authors wrote in a study published online today in the Proceedings of the National Academy of Sciences.
"Pre-clinical data have established that VISTA can suppress T cell activation and hinders the development of tumor-specific immunity," they explained, though "data on the functionality of VISTA+ cells in human cancer lacking."
The research, done through the National Cancer Institute- and Parker Institute for Cancer Immunotherapy-funded Pancreatic Cancer Moon Shot program, demonstrated that immune cells such as the CD3, CD4, and CD8 T cells were largely excluded from the PDAC tumors relative to the infiltration patterns in melanoma. And T cells in general appeared particularly inept when it came to infiltrating metastatic PDAC, the researchers said, pointing to "poor immunogenicity" in these tumors.
In contrast to the melanoma tumors, the microenvironment of PDAC tumors was also marked by enhanced levels of CD68+ macrophage white blood cells that expressed the VISTA immune checkpoint protein, suggesting it may be feasible to tackle PDAC by interfering with VISTA activity or by otherwise targeting these cells to boost immune activity against the cancer.
That suggestion was supported by the team's additional analyses, including CyTOF analyses on seven pancreatic tumor samples that pointed to roles for both PD-L1 and VISTA in independently staunching T cell activity towards the tumor.
Moreover, in a targeted analysis of nine T cell-inhibiting genes in samples from 23 untreated PDAC cases, the researchers reported that 12 patients with lower expression of VISTA and other immune inhibitory genes had a median survival time of 37 months compared to a median survival time of just 20 months in 11 patients with higher expression of the T cell-inhibiting genes.Â
In a statement, co-corresponding author and MD Anderson immunotherapy researcher Padmanee Sharma noted that there are "several antibodies to block VISTA under clinical development," though "[a]dditional research also needs to be done to see if we can come up with other targets for these VISTA-positive cells as well."