Investigating the mechanism behind tumor expression of CD58 – a costimulatory ligand on tumors that engages CD2 on T and NK cells, inducing cell adhesion, activation and cytolytic activity – researchers found that CMTM6 on the tumor cell surface directly interacted with CD58 and protected it from degradation. While CMTM6 also supported PD-L1 in a similar fashion, its support for CD58 was dominant, as co-blockade of PD-L1 and CD58 reduced antitumor T cell activation, and CMTM6 and CD58 were critical for the induction of antitumor T cell responses. Higher expression of CMTM6 and CD58 in patient biopsies was associated with favorable responses to ICB.
Contributed by Lauren Hitchings
ABSTRACT: 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 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.