Researchers led by Ludwig Lausanne’s Matteo Morotti, Alizee Grimm, Denarda Dangaj Laniti and Director George Coukos reported in an April publication in Nature their discovery of a mechanism by which the lipid prostaglandin E2 (PGE2) poisons the metabolism of tumor-targeting CD8+ T cells to serve as a checkpoint against their activity. Their study relied in part on the analysis of data and samples from clinical trials conducted in Lausanne of an immunotherapy known as adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL), or TIL-ACT. Those studies showed that TILs bearing markers of response to interleukin-2 (IL-2)—a factor essential to the functional vitality of T cells—were the ones that expanded best in culture, a finding that was verified in cell culture experiments. The researchers discovered that PGE2 disrupts the ability of T cells to respond to IL-2 by monkeywrenching the assembly of the IL-2 receptor’s component proteins. The resulting loss of IL-2 stimulation induces metabolic dysfunction, causing a functional lethargy in the TILs known as “anergy” and ultimately triggering ferroptosis, a type of programmed cell death. Disrupting that mechanism during the cell culture processes employed in TIL-ACT dramatically improved the therapeutic potential of transferred TILs in mouse models of cancer. Their findings were confirmed by a companion study in the same issue of Nature.
PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function
Nature, 2024 April 24