NOMIS researcher Susan Kaech and colleagues have identified how tumors cause immune cells to lose their ability to fight cancer, opening new avenues for therapies.
LA JOLLA—In order for cancer to grow and spread, it has to evade detection by our immune cells, particularly specialized “killer” T cells. Salk researchers led by Professor Susan Kaech have found that the environment inside tumors (the tumor microenvironment) contains an abundance of oxidized fat molecules, which, when ingested by the killer T cells, suppresses their ability to kill cancer cells. In a vicious cycle, those T cells, in need of energy, increase the level of a cellular fat transporter, CD36, that unfortunately saturates them with even more oxidized fat and further curtails their anti-tumor functions.
The discovery, published online in Immunity on June 7, 2021, suggests new pathways for safeguarding the immune system’s ability to fight cancer by reducing the oxidative lipid damage in killer T cells. Identifying factors like these that cause immune suppression in the tumor microenvironment can lead to the development of novel immunotherapies for cancer.
“We know that tumors are a metabolically hostile environment for healthy cells, but elucidating which metabolic processes are altered and how this suppresses immune cell function is an important area of cancer research that is gaining a lot of attention,” says Kaech, senior author and director of Salk’s NOMIS Center for Immunobiology and Microbial Pathogenesis. “Our findings uncovered a novel mode of immunosuppression in tumors involving the import of oxidized fats (AKA lipids) in T cells via the cellular fat transporter CD36, which impairs their anti-tumor functions locally.”
The burgeoning field of cancer immunometabolism studies how immune cell metabolism is reprogrammed within tumors and driven by alterations in nutrient availability. While scientists know that tumors accumulate fats—and that such accumulation is associated with immune dysfunction—the details of the relationship haven’t been clear.
Working with Joseph Witztum’s lab at UC San Diego and Antonio Pinto in the Salk Mass Spectrometry Core facility, the team established that tumors contain elevated amounts of several classes of lipid, and oxidized lipids in particular, which are generally found in oxidized low-density lipoproteins (LDLs), commonly considered “bad” fat. They then observed how killer T cells respond to the oxidized LDLs in tumors and found that killer T cells adapted to the tumor microenvironment by increasing CD36 on their surface and ingesting an abundance of oxidized lipids. Working with Brinda Emu’s lab at Yale University, they found this process served as a catalyst to drive even greater amounts of lipid oxidation internally in the killer T cells and ultimately repressed their defenses.
Continue reading this Salk Institute release
Read the Immunity publication: Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors
