Why are T cells so difficult to destroy solid tumors in immunotherapy?

The best hope for cancer immunotherapy is to boost our own immune cells in specific ways to prevent cancer cells from escaping our immune system
.
Although much progress has been made, immunotherapy is not always effective
.
Dr.
Jessica Thaxton of the immunotherapy group at the University of North Carolina Reinberg Comprehensive Cancer Center wanted to know why
.
One reason, she thinks, is that T cells produce a stress response
once they penetrate into solid cancers.

The latest research from Thaxton's lab, published in Cancer Research, shows in detail how the stress response of T cells can cause them to be unable to inhibit tumor growth
.
Thaxton's team found that T cells exposed to solid cancer environments naturally respond to stress, shutting down their function and limiting the T cells' ability to
kill tumors.
By controlling multiple proteins in the intracellular stress response pathway, Thaxton's team showed that it is possible to overcome the innate T cell stress response, allowing the immune system to stop the growth of cancer
.

At the heart of this research is a protein called PKR ER-like kinase (PERK), which is the main pressure sensor for all cell types, including T cells, but has not been well studied
in the context of immunity.
That is, when T cells are stressed — such as in the harsh environment created by cancer cells — PERK responds to stress in a way that stops the cells from secreting proteins to help the cells survive
.

Thaxton, senior author of the paper and associate professor of cell biology and physiology at the University of North Carolina School of Medicine, said: "Stopping protein translation has a protective effect in most cells and is part of the acute part
of the T cell stress response.
Everything in the scientific literature suggests that the acute part of the PERK-mediated stress response is designed to protect cells
in harsh environments.
”

But Thaxton's group hypothesized that this natural T-cell stress response would be detrimental to effective tumor immunotherapy
in the context of tumor suppression.

"T cells are among the most secreted cells in the body, producing about 800,000 proteins
per minute in an activated state against foreign invaders," she said.
For immunotherapy to be effective, T cells must secrete substances such as cytotoxic cytokines to kill tumor cells
.
”

She speculates that the PERK response may somehow block protein secretion, reducing the effectiveness
of T cells against tumors.

In 2019, Thaxton's lab created PERK-deficient T cells and injected these cells into tumor-bearing hosts, finding that T cells that cannot experience a stress response through PERK are very good at controlling tumor growth
.
Through animal models, the team also showed that the efficacy of clinically used immunotherapies can be improved by adding PERK suppression, further demonstrating that PERK can impair effective immunotherapy
.

This led her team to conduct experiments to determine whether PERK itself is responsible for poor control of T cell tumors, or whether other actors in the signaling pathway initiated by PERK may be responsible for inhibition of protein secretion in T cells, as proteins within cells work
through complex cascade interactions.

Thaxton's lab found that when PERK is activated, modifications to a molecule called p-eIF2 α cause T cells to temporarily stop protein synthesis
during a stress response.
When Thaxton's lab forced the p-eIF2 α to stop its natural function, the T cells continued to synthesize the protein and the T cells were able to continue controlling tumor growth
in mice.

"This work is part of our exploration of the PERK axis to understand the role
this pressure sensor plays in coordinating the function of T cells in cancer.
" Our goal is to discover the most effective therapeutic targets in the PERK cascade to develop unique pathways to improve the efficacy of immunotherapy," Thaxton said
.

Thaxton's research suggests that it is highly possible to genetically or pharmacally tune T cells to enhance their ability to fight cancer tumor cells
.
This work also demonstrates the importance of studying the basic cell biology and bioenergetics of cells at the forefront of
cancer treatment.

"We think it's important to understand from a molecular and cellular biologist's perspective why some immunotherapies aren't as effective as we thought," Thaxton said
.
"Until now, however, some basic cell biology principles and phenomena about how cells respond to stress have been overlooked in immune cells
.
"