Scientists Identify Possible Cause for Pancreatic Cancer Resistance
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Even though immunotherapies have seen incredible results for a variety of cancers, pancreatic tumors remain notoriously resistant to treatment. With five-year survival rates dropping to below 10%, this particular oncological issue is seen a priority.

MD Anderson Cancer Center researchers investigating new targets for current drugs have noticed an overexpression of the immune checkpoint VISTA on immune cells, especially macrophages, that infiltrated pancreatic tumors. The VISTA protein, or V-domain Ig suppressor of T cell activation molecule, is generally found in white blood cells and helps maintain peripheral tolerance.

Led by Padmanee Sharma, M.D., Ph.D.and 2018 Nobel Laureate Jim Allison, Ph.D, the team started comparing samples against melanoma tumors, the cancer that is most vulnerable to immune checkpoint blockade. They analyzed expression of nine immune inhibitory genes in 23 untreated surgically removed pancreatic cancer tumors and detected a significant difference.

Two categories were set up, one with 11 high-expression of inhibitory genes which corresponded to patients that had a median survival of 20 months compared to the 12 low expression genes that indicated a median survival of 37 months.

They also observed key distinctions in structure. Pancreatic tumors were composed of 30 percent malignant cells and 70 percent stroma, while those proportions were flipped in melanoma tumors. Stroma represents connective tissue which acts as a supportive framework for biological cells or organs.

In melanoma, you have a large area of malignant cells surrounded by a thin layer of stroma. With pancreatic cancer, it’s more like cancer cells, stroma, cancer cells, stroma blended”, explained Dr. Sharma.

As the T cells, which track down and destroy threats inside the body, were concentrated mostly in the stroma, researchers now believe that the tissue is in fact somehow hindering their effectiveness.

VISTA is mostly expressed on macrophages – “big eater” immune cells that engulf and digest microbes, cellular debris, and tumor cells as part of the immune response and have been known to deactivate T cells.

The team found a similar density of CD68-positive macrophages in both tumor types, in pancreatic cancer they were again concentrated in the stroma. Macrophages in the pancreatic tumors had much higher expression of VISTA.

Laboratory experiments confirmed their findings and showed that an active VISTA pathway decreased active T cell responses in the tumor to a greater degree than PD-L1 inhibition. This suggests treatment with PD-1/PD-L1 inhibition might fail because an untreated VISTA pathway still suppresses the immune response.