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VISTA Checkpoint Implicated in Pancreatic Cancer Immunotherapy Resistance


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Researchers have identified a new potential immunotherapy target in pancreatic cancer, which so far has been notoriously resistant to treatment with immune checkpoint blockade drugs effective against a variety of other cancers. A research team from The University of Texas MD Anderson Cancer Center found overexpression of the immune checkpoint VISTA on immune cells, especially macrophages, that infiltrated pancreatic tumors. Their findings were published by Blando et al in Proceedings of the National Academy of Sciences.1


VISTA is a potential therapeutic target in pancreatic cancer, and there are several antibodies to block VISTA under clinical development.
— Padmanee Sharma, MD, PhD

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“VISTA is a potential therapeutic target in pancreatic cancer, and there are several antibodies to block VISTA under clinical development,” said co-senior author Padmanee Sharma, MD, PhD, Professor of Genitourinary Medical Oncology and Immunology at MD Anderson. “Additional research also needs to be done to see if we can come up with other targets for these VISTA-positive cells as well.”

Present immune checkpoint inhibitors that unleash an immune attack on cancer by blocking programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) brakes on T cells have been ineffective against pancreatic cancer.

James Allison, PhD

James Allison, PhD

The team, led by Dr. Sharma and James Allison, PhD, Professor and Chair of Immunology at MD Anderson, set out to shed light on the infiltration of immune cells and expression of immunity-inhibiting checkpoints in pancreatic cancer by comparing those tumors to melanoma, the cancer that is most vulnerable to immune checkpoint blockade.

They first analyzed expression of 9 immune inhibitory genes in 23 untreated, surgically removed pancreatic cancer tumors and found the results separated the patients into 2 groups—11 with high expression of inhibitory genes and 12 with low expression.Those with low expression of immune inhibitors had a median survival of 37 months vs 20 months for the high-expression group, indicating a potential immune impact on overall survival.

Tumor Architecture

Pancreatic cancer tumors include a high density of stroma—nonmalignant supportive cells—whereas melanoma is at the other end of the spectrum with minimal stroma. These differences came into play in the team’s analyses. The pancreatic tumors were composed of 30% malignant cells and 70% stroma, whereas those proportions were flipped in melanoma tumors.

In melanoma, you have a large area of malignant cells surrounding a thin layer of stroma. With pancreatic cancer, it’s more like... cancer cells, stroma—blended.
— Padmanee Sharma, MD, PhD

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In addition to the vastly different ratio of stromal cells, the architecture of the tumor types also diverges, Dr. Sharma noted. “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.”

Analysis of 29 untreated pancreatic cancer tumors and 44 untreated melanomas found heavier penetration of attacking immune T cells in melanoma, as well as higher levels of cells expressing the inhibitory checkpoint molecules PD-1 and programmed cell death ligand 1 (PD-L1), which are successfully targeted by inhibitors to treat melanoma. However, pancreatic tumors had much higher expression of VISTA.

About a third of the pancreatic tumors had T-cell penetration roughly equal to that found in melanoma, but the T cells were concentrated mainly in the stroma of the tumors, rather than the malignant cells, whereas they were evenly distributed between cancer cells and stroma in melanoma.

VISTA and Macrophages

VISTA is predominantly expressed on macrophages and is known to deactivate T cells.

While the researchers found roughly equal 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.

A separate comparison of three types of pancreatic tumor—untreated primary, treated metastatic, and primary tumors pretreated before surgery—found low penetration of T cells in the metastatic tumors and elevated levels of VISTA in the untreated primary and metastatic tumors.

Analysis of seven pancreatic samples found that CD68-positive macrophages had distinct PD-L1 and VISTA pathways that inhibit immune response separately. Experiments with T cells taken from tumors of three patients with metastatic pancreatic cancer 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 immune response.

Future research will include exploration of combination therapy strategies to increase T-cell infiltration, possibly using anti–CTLA-4 checkpoint inhibition plus a VISTA antibody to target macrophages, Dr. Sharma said. 

DISCLOSURE: This research was funded by the immunotherapy platform, the Pancreatic Cancer Moon Shot, a grant from the National Cancer Institute, and the Parker Institute for Cancer Immunotherapy. The study authors’ full disclosures can be found at pnas.org.

REFERENCE

1. Blando J, Sharma A, Higa MG, et al: Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer. Proc Natl Acad Sci U S A 116:1692-1697, 2019.


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