CD8 T cells can recognize and kill cancer cells based on expression of (neo)antigens arising from genetic and epigenetic aberrations. Tumors commonly escape this immune surveillance through a variety of mechanisms that attenuate the activity of CD8 T cells in the tumor microenvironment. Although basic mechanisms such as impaired antigen presentation and expression of immunosuppressive surface molecules such as PD-L1 are well-established, the pathways that integrate these signals in CD8 T cells and ultimately determine their anti-tumor activity remain incompletely understood.
To systematically identify regulators that control the expansion and anti-tumor activity of CD8 T cells, we performed genome-scale proliferation- and FACS-based CRISPR screens in long-term cultured CD8 T cells and subsequently characterized candidate genes using focused CRISPR screens in tumor-specific CD8 T cells in vivo. As the most prominent hit, we identify the transcriptional repressor Capicua (CIC) as an important regulator of T cell fitness and anti-tumor immunity. Suppression of CIC enhances both, the expansion and effector functions of CD8 T cells, and thereby their anti-tumor activity. CIC has previously been characterized in embryonic stem cells as a RAF-MEK-ERK dependent transcriptional repressor. In CD8 T cells, we find that most direct transcriptional effects of the RAF-MEK-ERK signaling pathway are indeed controlled via CIC, which occupies a highly confined and conserved set of target genes that are de-repressed upon RAF-MEK-ERK stimulation. Loss of CIC leads to constitutive activation of these target genes and thereby enhances effector functions of CD8 T cells while rendering them fully insensitive to Mek inhibition. Taken together, our study uncovers CIC as a central effector of RAF-MEK-ERK signaling in CD8 T cells and implicates it as a candidate target for boosting their anti-tumor activity.