UCLA

Immune checkpoint blockade (ICB) targeting programmed cell death-1 (PD-1) has led to prolonged clinical responses among several patients with melanoma and other cancer types. ICB response relies on effective immune recognition and elimination of tumor cells. This depends on the successful presentation of tumor-specific antigens on surface major histocompatibility complex (MHC) class I molecules by tumor cells to the T-cell receptor of cytotoxic CD8+ T cells. Currently, both primary and acquired mechanisms of resistance remain significant barriers to expanding the therapeutic benefits of anti-PD-1 treatment. Several studies have stressed the critical role of antigen processing machinery (APM) defects in mediating resistance to ICB therapies. More specifically, aberrations of the β-2-microglobulin (B2M) gene, which encodes a critical component of the MHC class I molecule, were found to be enriched in patients with melanoma who progressed during therapy. Nevertheless, there are cases of patients with B2M-deficient tumors that respond to ICB, but the exact mechanism mediating this response is currently unknown. Presently, the exact effect of MHC class I APM alterations on anti-PD-1 therapy response requires further characterization and the cells mediating the anti-tumorigenic effects of PD-1 blockade in B2M-defective tumors have not been fully elucidated. In this work, we aim to holistically characterize alterations in components involved in class I antigen processing, presentation, and regulation in melanoma tumors, as well as to elucidate the main cell mediators of class I-deficient tumor removal in patient-derived biopsies and mouse models. Using a clinical dataset of patients with melanoma treated with ICB, whole-exome sequencing and bulk RNA-sequencing data from baseline tumor samples were analyzed to identify somatic class I APM alterations and evaluate correlative clinical outcomes, infiltrating immune cells, and gene expression patterns. Additionally, human melanoma cell lines and B2M-null mouse tumor models were utilized to validate these findings and further explore the impact of B2M and MHC class I defects on tumor intrinsic and extrinsic factors. Collectively, our findings may help offer alternative therapeutic targets and avenues for the treatment of tumors with class I-mediated ICB resistance.