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Pancreatic Cancer Immune Target Identified

1 year, 10 months ago

4518  0
Posted on Jan 15, 2019, 9 p.m.

Current immune checkpoint inhibitor therapies are largely ineffective against pancreatic cancer, but that could all change as an immune checkpoint molecule has been identified that could represent a promising immunotherapeutic target for this tumor type, as published in the Proceedings of the National Academy of Sciences.

Scientists from the University of Texas MD Anderson Cancer Center found that in pancreatic cancer V-domain immunoglobulin suppressor of T cell activation is preferentially expressed at high levels as compared to melanoma tumors. The team also provided a detailed analysis of immune infiltration in primary and metastatic pancreatic cancers which may help to direct immunotherapy strategies.

Prognosis for pancreatic cancer patients is low with a 5 year survival rate of less than 7%. ICT has helped to change cancer treatments in recent years, but not all tumor types respond well to current immune checkpoint inhibitors. The team compared immune infiltration in pancreatic cancer which doesn’t respond well to ICT with that of melanoma which does respond well in order to gain more insight into the immune architecture of pancreatic tumors; immune infiltration in primary untreated and primary neoadjuvant treated PDACs and metastatic PDACs were also compared. In particular where in TME immune infiltration was localized was analyzed to determine whether immune cells are localized in close contact with tumor cells, or within the tumor area, or in the stromal component of the tumor.

Expression of 9 recognized immune inhibitor genes in 23 untreated surgically removed pancreatic tumors were analyzed, results indicated patients could be categorized into 2 groups:11 with high expression of T-cell co-inhibitory genes; and 12 with low expression. Expression was inversely correlated with survival such that the median of survival of patient with tumors exhibiting low expression of T-cell co-inhibitor genes was 37 months compared to 20 months for those with high expression of the genes.

Pancreatic tumors are characterized by high density of stroma and non-malignant supporting cells; analyses found that pancreatic tumors were comprised of 30% malignant cells and 70% stroma, where as melanoma tumors were 30% stroma and 70% tumor. Comparing immune infiltration into untreated metastatic melanoma and untreated PDAC revealed melanoma tumors to have had higher density of CD3, CD4, CD8 cells, memory T cells, B cells, and regulatory T cells than that of pancreatic tumors. Close to ⅓ of the pancreatic tumors demonstrated T cell penetration roughly equal to that which was found in the melanomas; however in these pancreatic tumors the T cells were concentrated mainly in the stroma not within the tumor area, in melanoma tumors they were distributed evenly between the stroma and malignant cells.

Melanomas were found to demonstrate higher levels of cells expressing inhibitory checkpoint molecules PD-1 and its activating ligand PD-L1 in analysis of 44 untreated melanomas and 29 untreated pancreatic cancer tumors. Further investigation showed a higher density of CD68 expressing macrophages in tumoral components of melanoma TME compared to pancreatic tumors. Despite lower density of CD68+ macrophages, PDAC had significantly higher density of VISTA expression, which suggests that VISTA could be a potential immunotherapeutic target.

Additional separate comparison of 3 types of pancreatic tumors: untreated primary, treated metastatic, and primary tumors treated before surgery found low penetration of T cells in metastatic tumors and higher levels of VISTA in untreated primary and metastatic tumors.

CD68 positive macrophages were found to have had distinct PD-L1 and VISTA pathways to act to inhibit immune response separately in analysis of 7 pancreatic tumor samples; and T cells from tumors of 3 patients with metastatic pancreatic cancer showed an active VISTA pathway decreased T cell responses to a greater degree than PD-L1 inhibition, suggesting treatment with PD-1/PD-L1 inhibition might fail due to an untreated VISTA pathway suppressing immune responses. Blocking VISTA but not PD-L1 inhibited cytokine production via tumor infiltrating T cells. The team concluded that anti-VISTA antibodies may be an effective immunotherapeutic strategy for pancreatic cancer.

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