Insight into exhausted immune cells could open new doors for cancer therapy

The body’s immune T cells fight off foreign invaders, but in patients with cancer and chronic diseases, they get tired from that constant battle.

And it’s not just the body’s natural T cells that get exhausted.

Engineered cells known as CAR-T cells — which aim to home in on and attack tumor cells — can get worn out, too. Now, scientists have a clearer picture of what’s happening inside those tired T cells. We talked to researcher Dr. Nick Haining of the Dana-Farber Cancer Institute about the work, published this week in Science.

What’s the importance of studying T cell exhaustion?

It’s become increasingly clear in cancer and chronic diseases like HIV that T cells can recognize viral antigens, but they just don’t work very well. These so-called exhausted T cells seem to be one of the main reasons patients can’t get rid of their cancer or clear their infection.

T cell exhaustion seems to be a problem not only in natural T cells but also engineered CAR-T cells. Therapeutic CAR-T cells seem to work really well in blood cancers, but not so well in solid cancer or brain tumors. That’s because the CAR-T cells themselves become exhausted like natural ones.

What did you discover about those exhausted T cells?

We’ve known [that] exhausted T cells have a different pattern of gene expression — including high levels of [a receptor called] PD-1 — than their functional counterparts. We set out to address whether those two cells are actually functionally different.

So we used a new technique to map all the regulatory regions across the genome of T cells. Those regions are like thermostats — each one can be turned up or down. When we compared functional T cells and their exhausted counterparts, we found the molecular circuitry was fundamentally different in exhausted cells.

And if the wiring is completely different, that opens up a whole new way to engineer CAR-T cells so they don’t become exhausted. Rather than destroy a gene like PD-1 that you don’t like, you can destroy the thermostat that controls it. That’s important because PD-1 has a benefit.