T-bet and Eomesodermin are required for adaptive immunity against cancer (101.27)

Abstract

Abstract Cell-mediated adaptive immunity is very important in tumor immune surveillance and tumor vaccination. However, the genetic program underlying an effective adaptive anti-tumor immunity is elusive. T-bet and Eomes have been suggested to be master regulators of Th1 cells and CD8+ T cells. Whether they are important for anti-tumor immunity is controversial. Here we show that lack of T-bet and Eomes has resulted in profound defects in adaptive anti-tumor immune responses in both prophylactic and therapeutic settings. T-bet and Eomes are also important for CD8+ T cell activation without affecting T cell clonal expansion, the gaining of effector phenotype and cytolytic function. Unexpectedly, T-bet and Eomes are dispensable for IFNg production by CD8+ T cells under optimal Th1 differentiation conditions. However, they are necessary for suppressing alternative fates of CD8+ T cells. They drive Tc1 differentiation by preventing alternative CD8+ T cell differentiation to Tc17 or Tc2 cells. Surprisingly, T-bet and Eomes are not critical for the generation of systemic CTL activities against tumor cells. Instead, T-bet and Eomes are crucial for T cell migration and retention in the tumor site and elimination of solid tumors by CD8+ T cells through regulating chemokine receptors such as CXCR3 and IFNg expression in tumor microenvironment. Therefore, our study establishes T-bet and Eomes as key regulators of adaptive cell-mediated immunity against cancer.