What is it about?

The problem – ovarian cancer is broadly lethal: To date, treatments that activate the immune system to kill cancer have not worked well in most ovarian cancer patients. This study asked 1) what is stopping the immune system from killing ovarian cancer and 2) will treatments be more effective if they are combined? The approach – specifically boost tumor-killing immune responses: Immune cells called “T cells” can kill abnormal cells, and some of a patient’s own T cells may be able to recognize and kill cancer cells naturally. But, this response is usually not enough to control ovarian cancer. Our research genetically engineers large numbers of T cells that could better kill a patient’s tumor when used as therapy. Then, we use cancer models to discover ways to make engineered T cells better at killing cancer before giving the cells to patients. This article – hiding “stop signs” that block cancer killing: Cancer cells and other cells in tumors make proteins, called inhibitory molecules, that act like stop signs for T cells and prevent them from effectively killing the cancer. In some cancers, blocking one or two of these stop signs leads to better cancer killing, but blocking these proteins in ovarian cancer has not improved outcomes for most patients. Our research discovered that only blocking the stop signs may not be enough to improve ovarian cancer killing. In a mouse model of advanced ovarian cancer, tumor control only happened when engineered T cells were given, and mice with cancer survived the longest when they received engineered T cells and three "stop signs" were blocked. The results from these studies may lead to more effective treatments for ovarian cancer patients.

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Why is it important?

One of every 75 women in the United States will develop ovarian cancer in her lifetime, and one of every hundred will die from the disease. This mortality rate has changed very little in the last 30 years. Currently, the standard of care is surgery with chemotherapy, but tumors grow back in most of these patients and many tumors become resistant to chemotherapy. Too few people live five years beyond their diagnosis, and better treatments are urgently needed. Many solid tumors escape T cell killing using the same “stop signs” as ovarian cancer, so our findings may also be useful for improving immune therapies for other types of cancer, including other gynecological cancers, pancreatic cancer, and lung cancer.

Perspectives

T cell therapy has already shown great success against more than one type of blood cancer, and clinical trials have started to evaluate T cell treatments against solid tumors. Our lab has developed new ways to identify molecules on T cells (called T cell receptors, or TCRs) that bind specific molecules on tumor cells and activate T cells to kill those cancers. We can engineer T cells to target the cancer-associated protein known as mesothelin, which is abundant in ovarian cancer. These engineered T cells can kill ovarian cancer cells in mice, controlling tumor growth and increasing survival. Excitingly, human T cells engineered to target mesothelin were shown to be safe in a recent clinical trial, but the T cells did not survive in the tumors long enough to be effective. Our experiments revealed hurdles that T cells must overcome to beat ovarian cancer. The studies in this article suggest that a treatment approach combining engineered T cells and "stop sign" blockade may be needed for effective tumor control with immunotherapy.

Kristin Anderson
University of Virginia

Read the Original

This page is a summary of: Triple checkpoint blockade of PD-1, Tim-3, and Lag-3 enhances adoptive T cell immunotherapy in a mouse model of ovarian cancer, Proceedings of the National Academy of Sciences, September 2025, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2419888122.
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