A study led by Ludwig MIT’s Stefani Spranger explored how factors unique to the tumor-draining mediastinal lymph nodes (mLNs) compromise CD8+ T cell responses to lung cancer. Stefani’s lab had previously identified a gene expression signature in tumor-infiltrating T cells that is associated with an inability to target cancer cells. In the recent study, her team sought to understand the origins of that dysfunction. She and her colleagues reported in Immunity in February that the dysfunction originates in the mLNs, where tumor-targeting killer T cells should ordinarily be activated by antigen-presenting dendritic cells. Their studies revealed that Type 1 conventional dendritic cells (DC1s) fail to appropriately activate tumor-targeting killer T cells because they are directly suppressed by regulatory T cells (Tregs) in specific niches within the mLNs. The Tregs, the researchers found, are pushed by elevated levels of a factor known as interferon-γ (IFNγ) into a state in which they resemble T helper-1 (Th1) cells. IFNγ is produced in response to commensal bacteria that live in the lung. The researchers showed that the presence of Th1-like Tregs correlates to poor responses to checkpoint blockade therapy in patients. They also showed that in mouse models of lung cancer IFNγ-blockade reprogrammed Tregs out of the Th1-like state and restored CD8+ T cell-targeting of lung tumors.
Tissue-specific abundance of interferon-gamma drives regulatory T cells to restrain DC1-mediated priming of cytotoxic T cells against lung cancer
Immunity, 2023 February 2