New Immunotherapy Approach Reverses T Cell Exhaustion

Investigators have discovered an approach to reduce T cell exhaustion in immunotherapy-resistant tumors, according to a study published in Cell Reports. Blocking the activity of the protein P-selectin glycoprotein ligand-1 (PSGL-1), which promotes T cell exhaustion, can both slow exhaustion and allow the cell to return to normal functioning.

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“Slowing or reversing T cell exhaustion is a huge focus in cancer research, and many researchers are working on different ways to accomplish this,” said first author Jennifer Hope, PhD, assistant professor, Drexel University, in a press release.

Cancer or chronic disease causes constant stress on cells in the immune system. As a result, immune system T cells shut down, becoming “exhausted.” Without active T cells, the body cannot fight cancer or kill tumor cells. This is why an overarching goal in immunotherapy research is reverse T cell exhaustion, supporting immune function and fighting cancer.

PSGL-1 is a protein found in most blood cells. Investigators first discovered that PSGL-1 facilitates T cell exhaustion when studying mice who were deficient in PSGL-1. In their most recent study, they used an antibody that actively targets and blocks PSGL-1 activity in mice with immunotherapy-resistant melanoma. Not only did the treatment slow exhaustion, but it also transformed the exhausted T cells into functioning T cells, which significantly reduced tumor growth.

This therapeutic approach is so unique from other immunotherapies because it revives T cell function, Hope said in the press release. It also differs because it targets multiple aspects of the T cell exhaustion process.

Cancer can become resistant to treatment using only a single type of therapy, said senior author Linda Bradley, PhD, a professor in the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys, in the press release. So, although it could be an effective treatment on its own, “it also has tremendous potential to work synergistically with existing therapies,” Burnham said. Thus, it could make for an especially beneficial treatment for patients with immunotherapy-resistant forms of cancer.

Recognizing that a PSGL-1- blocking antibody could have therapeutic potential across an array of cancer types, the team also studied it in mice with mesothelioma. While using an antibody or recombinant protein as immunotherapy is not clinically approved for humans, this research could usher in a new immunotherapy approach that works for treatment-resistant types of cancer.

“The more tools at our disposal to slow down or reverse T cell exhaustion in different ways, the better chance we have of improving precision medicine and helping more people with cancer benefit from immunotherapy,” Bradley said in the press release.

Reference

Sanford Burnham Presbys. Reviving exhausted T cells to tackle immunotherapy-resistant cancers. News Release. May 3, 2023. Accessed May 5, 2023. https://www.eurekalert.org/news-releases/988211