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Researchers say T cells used in immunotherapy may be hindered by stress responses induced when encountering solid tumors. Getty Images
  • Immunotherapy is a treatment that uses biological substances derived from living organisms to treat cancer. It works by improving the immune system’s effectiveness in fighting off infections and diseases.
  • The primary aim of cancer immunotherapy is to enhance immune cells to prevent cancer cells from escaping the immune system’s control. However, it does not always work as expected.
  • Now, immunotherapy experts suggest that one reason immunotherapy may not always be effective could be the stress response encountered by T cells when they enter solid tumors.

In new research published in the journal Cancer Research, researchers explain how the stress response experienced by T cells can reduce their effectiveness at restricting tumor growth.

The researchers said they found that T cells that are subjected to the environment of solid cancers undergo a stress response that limits their abilities, hindering their capability to eliminate the tumors.

They said that by manipulating various proteins in the stress response pathway within T cells, it is possible to overcome the T cell’s intrinsic stress response and enable the immune system to fight against further tumor growth.

The research focuses on a protein called PKR ER-like kinase (PERK), which is important for sensing stress in all types of cells, including T cells.

However, until now, it hasn’t been closely looked at in relation to immunity.

When a T cell encounters cancer cells, PERK can react to the stressors, such as lack of glucose, an important nutrient for cells. This response leads the T cell to stop producing proteins, something T cells need to survive.

When a cell stops producing proteins, it’s a protective mechanism in most cells and is part of the T cell’s immediate response to stress. Previous scientific literature has reported that the immediate response through PERK helps cells survive in tough conditions.

However, the researchers in the current study said that this natural T cell response to stress would actually harm the effectiveness of cancer immunotherapy when it comes to stopping tumors.

The researchers proposed that the PERK response may inhibit protein secretion by T cells, making them less effective in fighting tumors. T cells produce around 800,000 proteins per minute 24 hours after activation against foreign invaders.

For immunotherapy to be effective, T cells must secrete cytokines, such as cytotoxic cytokines to kill tumor cells. Previous studies have shown that T cells without PERK were better at controlling tumor growth when transfused into tumor-bearing hosts.

The team also found that the effectiveness of immunotherapies could be improved by inhibiting PERK, proving that PERK interferes with successful immunotherapy.

Dr. Irina Sachelarie, a hematologist and medical oncologist at Memorial Care Cancer Institute in California who was not involved in this research explained the key findings to Medical News Today.

“This is an article of high relevance for T cell biology and T cell therapy in general,” she said. “T cell metabolism has already been shown to influence T cell therapy efficacy in the clinical setting.”

Dr. Judith O. Hopkins, the co-lead of the Novant Health Cancer Institute Breast Program, also not involved in this research, agreed.

“One of the reasons that cancer is so difficult to prevent is the complex interaction between individual cancer cells and the tumor microenvironment. T cells are but one component of a complex immune system,” she told Medical News Today.

Both tumor cells and the T cells present in the tumor need glucose in order to thrive and they compete for this nutrient. Lack of glucose contributes further to attenuation of T cell function. Different states of T cell metabolism are correlating with responders versus nonresponders post T cell therapy. A robust metabolic function of T cells is found in patients with better clinical response.

Dr. Irina Sachelarie

Sachelarie also noted how this research has “identified a novel mechanism for improving T cell function. One of the mechanisms of action through which T cells can restore function in a low glucose environment is an enzyme (PERK = PKR ER-like kinase), which can modify a protein (eif2) to overcome inhibition of T cell metabolism.”

“PERK is a stress sensor for all cells and for T cells as well. When T cells are under stress (like when they must fight cancer cells), PERK causes T cells to stop secreting proteins in order to protect and help the T cell survive. But the loss of protein secretion (cytokines) leads to loss of function of T cells and likely impairs the effect of immunotherapy on cancer cells,” she explained.

“The immune system plays a very important role in regulating tumor growth. Malignant cells can escape the immune system and as a result, they proliferate and spread to other parts of the body (metastasize). Cancer immunotherapy is a novel way of treating cancer by enhancing or modifying the patient’s immune response to find and fight these cancer cells. Although greatly effective, sometimes immunotherapy does not work as well as expected. This [research] suggests that one of the reasons why immunotherapy might not work is the stress response experienced by T cells once they infiltrate solid cancers.”

– Dr. Irina Sachelarie

Sachelarie explained that these are still early findings in the discovery phase and they will need to be translated into preclinical studies to establish their potential usefulness. Therefore, further research is needed.

Dr. Santosh Kesari, Ph.D., a neuro-oncologist and director of neuro-oncology at Providence Saint John’s Health Center in California who was also not involved in the study, explained that “the immune system is very critical in many aspects of health including the development of cancer. This study expands the understanding of how competition for local nutrition within tumors can affect immune function.”

“The authors have identified a new approach to boosting the immune response by increasing nutrient availability for the immune cells using different classes of drugs,” Kesari told Medical News Today.

This study highlights a new approach for cancer immunotherapy which may lead to improved cancer treatments in the future.

Dr. Santosh Kesari