Targeting ST2 expressing activated regulatory T cells in Kras-mutant lung cancer.

Oncogenic KRAS-mutant lung cancers remain treatment refractory. A better understanding of the immune response of KRAS-mutant lung cancers is required to facilitate the development of potential therapeutic strategies. Regulatory T cells (Tregs) are a subset of immune cells that promote tumor progression through suppressing anti-tumor immune response. Here, we used Kras lung cancer mice to examine the characteristics of tumor-infiltrating Tregs. In tumor-bearing animals, Tregs are increased during tumor progression. Of note, a majority of Tregs that localized in lung tumors of Kras-mutant mice expressed ST2, a receptor for IL-33, which are different from Tregs in secondary lymphoid organs. To investigate the function of local Tregs influencing immune response in primary lung tumor development, we used anti-ST2 antibody to deplete Tregs in lung tumors of Kras-mutant mice. Treatment of Kras-mutant mice with anti-ST2 antibody resulted in depletion of activated Tregs in lung tumor while leaving Tregs in secondary lymphoid organs intact. Also, localized Tregs depletion led to a significant reduction in lung tumor burden. Immune response after Tregs depletion in tumors showed restoration of NK cell activity and enhanced Th1 activity, with increased CD8 cytotoxic T cell response. In addition, we found that the M2 macrophage signature in lung tumors was suppressed upon Tregs depletion, accompanied by upregulation of surface expression of MHC-II molecules and reduced expression of , and . These data suggest that therapeutic strategies targeting activated Tregs in lung cancer have the potential to restrain tumor progression by enhancing anti-tumor immunity.