Among the T lymphocytes that infiltrate tumors (TILs), a species known as “terminally exhausted” TILs is best equipped to detect and destroy cancer cells. Its members are, however, functionally disabled, prone to self-destruction and unresponsive to current immunotherapies. A study led by Ludwig Lausanne’s Ping-Chih Ho and Li Tang of the École Polytechnique Fédérale de Lausanne examined whether an engineered, long-lived version of the immune factor IL-10 (IL-10/Fc) could revive these chronic underperformers. They reported in May in Nature Immunology that adding IL-10/Fc to adoptive cell therapy (ACT)—the infusion of T cells to treat cancer—boosted the number and functionality of terminally exhausted TILs in a mouse model of melanoma and led to tumor regression and cures in 90% of treated mice, compared to limited regressions with IL-10/Fc alone and none with ACT alone. Notably, 80% of surviving mice developed an immune memory for the cancer. Ping-Chih and colleagues also tested IL-10/Fc on CAR-T cells, which are engineered to target cancer cells bearing specific markers, and achieved cures in roughly 90% of mice implanted with colon tumors. IL-10/Fc, they showed, acts specifically on terminally exhausted TILs, reprogramming their metabolism in a manner that induces sweeping changes in their gene expression programs, driving their activation and proliferation.
This article appeared in the August 2021 issue of Ludwig Link. Click here to download a PDF (2MB).