Tackling immune escape: identifying novel targets and pathways involved in the regulation of CD155 in melanoma

Abstract

Melanoma is a highly aggressive form of skin cancer. While targeted therapies show a strong initial response, resistance remains a problem resulting in a five-year progression free survival rate of only 19 %. Immunotherapies provide a better long-term response but only in a small subset of patients. Therefore, there is an urgent need to better understand resistance mechanisms to optimize existing therapies or develop novel therapies. <br/>

CD155 is an adhesion molecule of the Nectin-like family with an intrinsic role in promoting tumor growth and extrinsic immunomodulatory functions as a ligand for the inhibitory immune checkpoints TIGIT and CD96, as well as the activating receptor CD226. CD155 is overexpressed across many different cancer types, and patients with overexpression have poor clinical outcome. Furthermore, CD155 is low expressed on healthy tissue making it an interesting target for immunotherapies. Our lab has recently shown that CD155-expressing tumor cells downregulated CD226 on tumor infiltrating CD8+ T cells, which rendered tumorinfiltrating T cells dysfunctional and contributed to resistance to cancer immunotherapies. Little is known about the intrinsic mechanisms regulating CD155 expression in cancer. <br/>

We have characterized CD155 in a panel of human melanoma cell lines harbouring different oncogenic driver mutations, and performed a genome-wide CRISPR knock-out screen to identify novel pathways and potentially druggable molecules involved in the intrinsic regulation of CD155. <em>DYRK1A</em> was identified and validated as an intrinsic regulator of CD155 surface expression. In addition, <em>DYRK1A</em> and the PI3K/AKT pathway were shown as interesting pharmacological therapeutic targets as our data showed that inhibition of the PI3K/AKT pathway reduced CD155 surface expression levels in a <em>BRAF</em>-mutant human melanoma cell line. Thus, our data provide the rational to further explore the use of DYRK1A or PI3K/AKT inhibitors alone or in combination with immune checkpoint blockade for the treatment of cancer overexpressing CD155. More validation of these findings might enable us to reduce or completely abolish CD155 expression in cancer cells in order to improve the efficacy of cancer immunotherapies.