Scientists break the mystery of the cause of immunotherapy failure

In this study, OSUCCC – James researchers sought to answer a long question: Why are the T cells, which are decisive to combat inflammation and cancer recognition, become “stressful” and sometimes lose their effectiveness?

In this study before the comprehensive clinical, researchers revealed that there is a hidden weakness in the exhausted T cells: they are mired in the uneven proteins that ignite the previously unrecognized stress path, and is now called Texpsr (the toxic stress response of protein in the exhaustion of T cells).

Unlike the normal strain responses that slow the production of protein to help cells restore balance, Texpsr causes protein synthesis to an increase in excess. The result is an uncompromising accumulation of wrong proteins, stress granules, and toxic cords – similar to amyloid plaques seen in Alzheimer’s disease. This excessive load of T -cells is disabled in their ability to attack tumors.

Nature Reviews ImmunologyThe leading opinion magazine in this field described this phenomenon as a “toxic shock to proteins.” Fightly, when the researchers prevented the main engines of Texpsr in pre -clinical models, the exhausted T cells regained their function and the immunotherapy of cancer became significantly more effective.

“Total cell exhaustion is the largest barrier for immunotherapy. Our study results provides a sudden and exciting answer to this basic problem and can be decisive to improve future scientific progress in the field of engineering drug treatments for the use of the immune system.

Lee, who held the position of Deputy Director of Research, has studied translation in OSUCCC – James, and holds the Klotz Memorial Chair in Cancer Research, the link between protein folding and immunity for more than three decades. He stressed: “The researchers around the world deal with the exhaustion of T cells by studying genetics, creation, metabolism and others, but the role of protein quality control has been overlooked to a large extent-so far.”

Ohio State Cancer Research also found that high levels of Texpsr in T -cells of cancer patients were associated with bad clinical responses to immunotherapy. This indicates that TEXPSR targeting can be a new way to enhance cancer treatment in clinics.

“When the T -cells become exhausted, they continue to create molecular weapons but destroy weapons before they can do their job,” said Yi Wang, the first author and a doctorate in Li Lab.

The team’s results reveal that this self -stress cycle is the main driver of T -cell exhaustion, which ultimately disrupts the function of these immune cells. It is worth noting that the mechanism has been validated in the multiple clinical and clinical cancer models – including the lung, bladder, liver cancer and leukemia – with highlighting its extensive importance through various types of cancer.

He and his colleagues reach their results in the last issue of nature.