Why don’t T cells destroy solid tumors during immunotherapy?
The great hope of cancer immunotherapy is to bolster our own immune cells in specific ways to keep cancer cells from evading our immune system. Although much progress has been made, immunotherapy does not always work well. Jessica Thaxton, PhD, MsCR, in the immunotherapy group at the UNC Lineberger Comprehensive Cancer Center, wants to know why. She thinks one reason is the stress response experienced by T cells once they infiltrate solid cancers.
The Thaxton lab’s latest work, published in the journal Cancer Research, shows in detail how the stress response in T cells can lead to their inability to curtail tumor growth. Thaxton’s group found that T cells exposed to the environment of solid cancers undergo a natural response to stress that shuts off their function, limiting T cell ability to kill tumors. By manipulating multiple proteins in the stress response pathway inside T cells, Thaxton’s team showed that it was possible to overcome the intrinsic T cell stress response to allow the immune system to thwart cancer growth.
At the center of this research is a protein called PKR ER-like kinase (PERK), which is a major stress sensor for all cell types, including T cells, but has not been deeply studied in the context of immunity. That is, when a T cell is under duress — like when faced with the hostile environment created by cancer cells — it is PERK that responds to the stress in a way that causes cells to stop secreting proteins in an effort to help the cell survive.
“Halting protein translation is protective in most cells and is part of the acute arm of the T cell’s stress response,” said Thaxton, senior author of the paper and associate professor of cell biology and physiology at the UNC School of Medicine. “Everything in the scientific literature indicates that the acute arm of the PERK-mediated stress response aims to protect cells in hostile environments.”
But Thaxton’s group hypothesized that — in the context of tumor suppression — this natural T cell stress response would be detrimental to effective tumor immunotherapy.
“T cells are among the body’s most highly secretory cells, producing approximately 800,000 proteins per minute in states of activation against foreign invaders,” she said. “In order for immunotherapy to be effective, T cells have to secrete things such as cytotoxic cytokines in order to kill tumor cells.”
She postulated that the PERK response could be halting protein secretion in a way that made T cells less effective at combating tumors.
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