Cancer cell surrounded by therapeutic antibodies and cytokines among normal cells
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The location of cytotoxic T cells, in and around tumors, may help predict lung cancer patient survival and treatment response, according to work from University of Edinburgh researchers. Their findings, they say, could help to pave the way for improved immunotherapies. Such treatments are revolutionary in their ability to cure some patients with previously incurable cancer, but they fail in 80 per cent of cases.

The study appears in the Journal for Immunotherapy of Cancer. The senior author is Ahsan R. Akram, Fellow at the University of Edinburgh’s Centre for Inflammation Research.

Lung cancer is one of the most common cancers worldwide and is the leading cause of cancer-related deaths. It is often diagnosed at an advanced stage when conventional treatments are more likely to fail.

Immunotherapy works wonders in a small number of patients, and the world market for these drugs is estimated to be worth more than $100B. These drugs boost the activity of cytotoxic T cells, but these cells can become “exhausted” when battling tumors. As tumors grow, they escape destruction in several ways, including interfering with the activity of T cells.

This team examined tumor tissue from 162 patients undergoing surgery for non-small cell lung cancer (NSCLC), which accounts for more than 80 percent of lung cancer cases.

They showed that high levels of two enzymes, (CD39 and CD73), on the surface of many different types of immune cells, were associated with reduced patient survival if found in tissue near the tumors. These are ectonucleotidases, extracellular enzymes that hydrolyze purine and pyrimidine nucleotides, and play a key role in inflammation. To stop T cells from becoming overactive when fighting an infection levels of these enzymes are raised.

The team found that both the location and types of T cells that express these enzymes could also play an important role in helping to predict a patient’s prognosis and the success of immunotherapy.

High levels of CD39 on the surface of cytotoxic T cells located inside tumor nests—clusters of cancer cells—were associated with increased patient survival and a better response to immunotherapy. In contrast when the same CD39 cytotoxic T cells were found outside of tumors, in a region called the stroma, they did not affect patient survival. High levels of CD39 on the surface of regulatory T cells, which normally prevent the immune system from becoming overactive, were associated with reduced survival.

The findings were consistent even when other factors were taken into consideration—such as a patient’s age, tumor size and whether they received chemotherapy in addition to surgery.

Understanding the mechanisms that suppress T cells and control their location could improve immunotherapy outcomes and better predict which patients will benefit from them, the researchers say.

Akram said, “This study helps us to understand that we need to know the types of T cells in the cancer and their location within the tumors to begin to appreciate the complexity we are dealing with. We hope these results will lead to more research in this area, and in the future could help to identify patients who will do well with immunotherapies, as well as identifying earlier those that may not, so alternative treatments can be tried.

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