The dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current ca...Show moreThe dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current cancer immunotherapies, a deficiency in costimulatory signals can render these therapies futile. CD58, a costimulatory ligand, plays a crucial role in antitumor immune responses, but the mechanisms controlling its expression remain unclear. Using two systematic approaches, we reveal that CMTM6 positively regulates CD58 expression. Notably, CMTM6 interacts with both CD58 and PD-L1, maintaining the expression of these two immune checkpoint ligands with opposing functions. Functionally, the presence of CMTM6 and CD58 on tumor cells significantly affects T cell-tumor interactions and response to PD-L1−PD-1 blockade. Collectively, these findings provide fundamental insights into CD58 regulation, uncover a shared regulator of stimulatory and inhibitory immune checkpoints, and highlight the importance of tumor-intrinsic CMTM6 and CD58 expression in antitumor immune responses. Show less
In this thesis I have firstly applied gene transfer technologies to the redirection of T cell specificity, by trying to overcome limitations related to non-viral gene transfer systems. In the... Show moreIn this thesis I have firstly applied gene transfer technologies to the redirection of T cell specificity, by trying to overcome limitations related to non-viral gene transfer systems. In the second part of my PhD work, I focused on genetic screens, which, I applied to understanding molecular mechanisms of escape from T cell attack and to reveal mechanisms of PD-L1 regulation. The work presented in this thesis may on the one hand facilitate the clinical application of non-viral-based gene transfer systems in T cells. On the other hand, the more fundamental discoveries related to IFN-γ-mediated tumor cell killing and PD-L1 regulation may help to further understand resistance toward immunotherapies and how to overcome them. Show less
