Epigenetic control of CD1D expression as a mechanism of resistance to immune checkpoint therapy in poorly immunogenic melanomas

Abstract

Immune Checkpoint Therapies (ICT) have revolutionized the treatment of metastatic melanoma. However, only a subset of patients reaches complete responses. Deficient β2-microglobulin (β2M) expression impacts antigen presentation to T cells, leading to ICT resistance. Here, we investigate alternative β2M-correlated biomarkers that associate with ICT resistance. We shortlisted immune biomarkers interacting with human β2M using the STRING database. Next, we profiled the transcriptomic expression of these biomarkers in association with clinical and survival outcomes in the melanoma GDC-TCGA-SKCM dataset and a collection of publicly available metastatic melanoma cohorts treated with ICT (anti-PD1). Epigenetic control of identified biomarkers was interrogated using the Illumina Human Methylation 450 dataset from the melanoma GDC-TCGA-SKCM study. We show that β2M associates with CD1d, CD1b, and FCGRT at the protein level. Co-expression and correlation profile of B2M with CD1D, CD1B, and FCGRT dissociates in melanoma patients following B2M expression loss. Lower CD1D expression is typically found in patients with poor survival outcomes from the GDC-TCGA-SKCM dataset, in patients not responding to anti-PD1 immunotherapies, and in a resistant anti-PD1 pre-clinical model. Immune cell abundance study reveals that B2M and CD1D are both enriched in tumor cells and dendritic cells from patients responding to anti-PD1 immunotherapies. These patients also show increased levels of natural killer T (NKT) cell signatures in the tumor microenvironment (TME). Methylation reactions in the TME of melanoma impact the expression of B2M and SPI1, which controls CD1D expression. These findings suggest that epigenetic changes in the TME of melanoma may impact β2M and CD1d-mediated functions, such as antigen presentation for T cells and NKT cells. Our hypothesis is grounded in comprehensive bioinformatic analyses of a large transcriptomic dataset from four clinical cohorts and mouse models. It will benefit from further development using well-established functional immune assays to support understanding the molecular processes leading to epigenetic control of β2M and CD1d. This research line may lead to the rational development of new combinatorial treatments for metastatic melanoma patients that poorly respond to ICT.

Keywords: Anti-PD1; CD1d; DNA methylation; MHC-I; SPI1; immune checkpoint therapy; melanoma; β2M.