Immune responses in young mice cause early T cell exhaustion against tumors

T cells live by the mantra “lose the battle, win the war.” A quick, strong T cell response is beneficial when facing an acute infection. Children’s T cells rapidly combat microbial intruders. Their strong, naïve immune system’s knee jerk reaction to invaders is the main reason that they produce more antibodies in response to vaccines and often have mild symptoms with COVID-19. 

But an over-the-top inflammatory response is often the reason that COVID-19 turns lethal. If T cells notice that their battle with an intruder rages too long, they lower their defenses and permit low level infections. But this strategy won’t win the war against cancer, which often becomes a long-term resident in its host.

“Once [T cells] enter the tumor where there's a lot of antigens around, they'll exhaust faster,” said Ardiana Moustaki, a cancer immunologist at St. Jude Children’s Research Hospital and first author of a new study published in Science Immunology. “Their cytotoxicity goes down and their ability to secrete cytokines goes down. That's how they kill, so when we say they're exhausted, they're functionally exhausted and therefore dysfunctional.”

Moustaki and her team recently reported that T cells in young mice with cancerous tumors become exhausted and die more quickly than those in older mice with tumors (1). This suggests that immunotherapy treatments may be less effective in children with cancer, although comparisons between older and younger people with tumors in a clinical setting is needed.

“It’s a beautiful study,” said Nick Haining, chief scientific officer and co-founder of the programmable T Cell therapy company Arsenal Biosciences who was not involved in this study. “It’s counterintuitive because you often think about young immune systems being healthier than old immune systems. But what they did was they looked to see, well, what are the cells that are stimulating the T cells?”

T cells aren’t solely in charge of their fate. They require two separate calls to duty. First, immune cells on the front line recognize dead cancer cells circulating in the body, engulf them, and present them to T cells. In response, the T cells rapidly proliferate and march toward the tumor. 

Once T cells invade the tumor, antigen presenting cells such as the Pacman-like macrophages that engulf cancer cells and debris present proteins specifically expressed by the tumor cells via receptors known as the major histocompatibility complex (MHC), directing them to their intended target. “It's not only about T cells,” said Moustaki. “Having a holistic view of the entire system and how communication between the different cell types is established is important.”

In the new study, Moustaki and her team set out to understand how the relationship between T cells and macrophages affected T cell response in the tumors of old and young mice. The researchers expressed a viral antigen tagged with a red fluorescent molecule in the tumor cells so that when a macrophage devoured a tumor cell, it would glow red. The tumor cells also lacked MHC, making macrophages the only cells within the tumor capable of activating T cells. 

The macrophages glowed a brighter red in the tumors of younger mice than in those of older mice. The T cells also expressed higher levels of markers of T cell exhaustion such as the transcription factor thymocyte selection-associated HMG BOX 1 (TOX1). The exhausted T cells were dysfunctional as well, producing significantly less cytokines than T cells in the older mouse tumors. 

The researchers confirmed that this exuberant, exhaustion-causing T cell response held true in humans as well. They examined tumor samples collected from patients and found higher levels of markers for exhausted T cells than in peripheral blood samples from healthy children.

Haining is excited to see what the team does next. He explained that childhood tumors have a much lower mutational burden than tumors from adults, which makes this result quite surprising. The high number of mutations in adult tumors results in misplaced proteins that may act as antigens to activate T cells. But that’s not what Moustaki and her team saw.

“What are those T cells seeing? If they’re not seeing new antigens, what are they seeing?” asked Haining. “It may be that not only are the T cells seeing new epitopes in solid tumors, but they may actually be seeing auto antigens that are being recognized in tumors. Some increasing circumstantial data from other sources suggest that might be true.”

Moustaki thinks that it will take efforts from multiple research teams to find out what these T cells see. The best place to understand the complexities of the tumor-driven immune response in pediatric patients and what it could mean for the efficacy of immunotherapies may not be in the lab, but in the clinic.

“There are not many studies comparing clinical outcomes from immunotherapy in adults versus young people,” said Moustaki. “It is important to consider that the young immune system has its own balance.” 

Reference

Moustaki et al. Antigen cross-presentation in young tumor-bearing hosts promotes CD8+ T cell terminal differentiation. Sci Immunol  7, eabf6136 (2022).