One of the main goals of immunotherapy is to reverse T cell fatigue to boost the immune system’s ability to clear cancer cells
Published Date – Mon 08 May 23 08:40 AM
Representative images.Photo: Arnie
La Jolla (California): When the immune system’s T cells are constantly stressed by cancer or other chronic diseases, they suffer from a process called T cell fatigue. Without functional T cells that attack tumor cells, our bodies cannot fight cancer.
One of the main goals of immunotherapy is to reverse T cell fatigue to boost the immune system’s ability to clear cancer cells.
Melanoma researchers at Sanford Burnham Prebys have devised a new way to do just that. Their technique, just published in Cell Reports, reduces T cell fatigue even in cancers resistant to clinically approved immunotherapies. It also prevents T cell exhaustion.
“Slowing or reversing T cell exhaustion is a huge focus of cancer research, and many researchers are investigating different ways to achieve this goal,” said first author Jennifer Hope, Ph.D., who completed the study as a postdoctoral fellow at Sanford Burnham Prebys, now an assistant professor at Drexel University.
“This new approach may be a viable treatment on its own, but it also has great potential to be synergistic with existing therapies.” Although immunotherapies targeting T cell depletion have already been established, this new approach is unique in that it targets several different aspects of the process simultaneously. This means it could help people overcome resistance to the various anti-cancer immunotherapies currently available.
“A fundamental philosophy of modern cancer treatment is not to rely on monotherapy, as this can lead to cancers becoming resistant to that therapy,” said senior author Linda Bradley, Ph.D., a professor in the Institute of Cancer Metabolism and Cancer Research. Microenvironment Program at Sanford Burnham Prebys. “The more tools we have at our disposal to slow or reverse T-cell exhaustion in different ways, the better our chances of improving precision medicine and helping more cancer patients benefit from immunotherapy.”
Their method relies on a protein called PSGL-1, which is present in most blood cells. By studying mice genetically deficient in PSGL-1, the researchers determined that this protein helps promote T cell exhaustion, a major obstacle to effective anticancer immunity.
The researchers then used an antibody to block the activity of PGSL-1 in mice with immunotherapy-resistant melanoma. They found that targeting PSGL-1 slowed the process of T cell exhaustion and helped the exhausted T cells revert to functional T cells. Both of these effects significantly reduced tumor growth in mice.
“Compared to existing immunotherapies, this approach is unique in that it directly alters the way T cells are depleted and helps them regain function,” Hope said. “I think that’s going to be critical in terms of its translational potential.”
The researchers were also able to replicate the effect in mice with mesothelioma, suggesting that the approach could be applicable to a variety of cancers. Although the treatment they used in this study is not yet suitable for clinical use in humans, the overall approach to immunotherapy using antibodies or recombinant proteins is well established. That means translating these results to cancer patients may just be a matter of time and testing.
“Once we’ve done all the necessary science, this could be really valuable, and even life-saving, for many cancer patients who are resistant to current treatments,” Bradley said. “We’ve got a long way to go.” way to go, but I’m optimistic we’re doing something game-changing.”
