The most exhausted T-cells recognize tumor cells best

Read their paper that was published in Nature Medicine on June 11th 2018

Cancer immunotherapy is aimed at boosting the patient's own immune system to fight cancer cells. Immunotherapy is now a standard therapy for advanced-stage non-small cell lung cancer and 25% of the patients show - sometimes long-term - clinical responses to this therapy. But why do these patients respond well whereas the majority doesn't?

A better understanding of the differences between these patient groups may allow clinicians to determine in advance which patients are more likely to benefit from immunotherapy. Other patients may then be better off with another type of treatment and will be spared the side effects of immunotherapy.  In addition, in view of the high costs of cancer immunotherapy for lung cancer (over 80% of all lung cancer is non-small cell lung cancer), it would be of value to only treat those patients who can be expected to benefit.

Daniela Thommen: 'But the most fundamental reason for studying this is the following: the moment you understand why some patients do not respond, you may try to solve the issue and treat a broader range of patients.'

To answer this question, Thommen analyzed the T cells in tumor biopsy material from a group of patients with stage 4 non-small cell lung cancer and compared their properties with clinical outcome. These patients, who were followed up to two years, were treated with so-called checkpoint inhibitors (or PD-1 blockade). This is now a broadly used form of cancer immunotherapy, aimed at reinvigorating T cells (CD8+ T cells) that have lost their ability to kill cancer cells.

Checkpoints and checkpoint inhibitors

Checkpoints are molecules on the surface of T cells that regulate the immune response and prevent T cells from killing innocent cells in the body. Cancer cells sometimes bind to these checkpoints in order to avoid being attacked by T cells. Checkpoint inhibitors are aimed at preventing cancer cells from doing this.  

T cells scan the body, recognize deviant cells and kill them. They do not only recognize cells infected by foreign intruders, such as viruses, but also recognize cancer cells for a number of human cancers, including non-small cell lung cancer.

It was already known that in chronic viral infections, T cells differ in their functionality. Thommen: 'I wanted to know whether this is also the case in cancer. And, if so, the next question would be if this can help to identify patients who are likely to respond to immunotherapy.'

The team discovered that the best way to differentiate between T cells in non-small cell lung cancer is by looking at the number of PD-1 checkpoint molecules on the cell surface. They saw that T cells that are crowded with these checkpoints on their surface, recognize the tumor cells best.  

Moreover, in the cohort of non-small cell lung cancer patients, the presence of these checkpoint-enriched T cells was strongly predictive for both response and survival. 'The predictive potential outperforms classical diagnostic tests in this patient cohort', says Thommen.

This specific population of checkpoint-enriched T cells stood out in a number of ways. Firstly, they were the only population of T cells that could strongly recognize tumor cells. Secondly, on the downside, they were the most dysfunctional T cell population in the tumor, expressing a series of other checkpoints next to PD-1. However, on the upside, they gained a new functionality in return, recruiting new T cells to the tumor micro-environment.

'We don't really know what makes them do this', says Thommen. 'It may be something in the tumor. Or it may be lack of nutrients at the tumor site. This is something we aim to further study in the coming period. The researchers also intend to validate the value of the most dysfunctional T cells as a biomarker for immunotherapy response in an independent patient cohort. Finally, they intend to study whether the T cells will flip back into their original function upon treatment.

Daniela Thommen e.a., 'A transcriptionally and functionally distinct PD-1⁺ CD8⁺ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade'
Nature Medicine  online publication, 11 June 2018

Links:

• The news story of the Swiss National Science Foundation
  
• Daniela Thommen
• Ton Schumacher Group at the Netherlands Cancer Institute
• Ton Schumacher Group at Oncode Institite

This work was supported by grants from the Swiss National Science Foundation, the Research Funds University of Basel,the Lichtenstein-Stiftung,the FAG-Basel,the Dutch Cancer Society and the European Research Council.