Abstract 6635: Lipid and glycolipid antigen presentation faults as a mechanism of resistance to immune checkpoint therapy in poorly immunogenic melanomas

Abstract

Abstract Introduction: Cold tumors are characterized by lacking infiltration of antitumor T cells. These tumors are universally refractory to immune checkpoint therapies (ICT). While poor T cell infiltration has been partly ascribed to low tumor mutational burden (TMB), TMB doesn’t necessarily exclude immunogenic responses nor ensure a response to ICT. Mechanisms of T cell exclusion in tumors with sufficient TMB may be caused by molecular failure of the antigen processing and presentation (APP), which impacts T cell generation. It was previously described that loss of heterozygosity (LOH) of an essential component of the MHC class I molecule, the beta-2-microglobulin (B2M), is associated with low antigen presentation, tumor T cell infiltration, and ICT resistance in melanoma. Here we provide further insight into APP and ICT response in melanoma. Methods: Transcriptomic analysis and visualization of genomic data from the GDC-TCGA skin cutaneous melanoma (SKCM) study were performed using the Xena platform. Four anti-PD1 metastatic melanoma cohorts were normalized with transcripts per million units. STRING protein-protein interaction analysis was performed in the human database with 11 nodes and 39 edges. Nanostring transcriptomic data from metastatic uveal melanoma (mUM) was revisited from our previous publications for Spearman’s correlational and group analysis of APP signatures amongst ICT responders and non-responders. Results: In an expanded analysis of 4 normalized anti-PD1 treated metastatic melanoma cohorts (n=272), we confirmed that transcriptomic levels of B2M are significantly reduced in non-responders. Moreover, STRING protein-protein interaction analysis of B2M revealed CD1D as a potential molecular partner of B2M. We, therefore, observed that CD1D transcriptomic expression is not only reduced in anti-PD1 poor responders but is a survival prognosticator in primary tumors from the GDC-TCGA study. Interestingly, CD1D expression is also significantly reduced in poorly immunogenic mUM tumors, a cancer type regarded as universally refractory to ICT. Conclusions: These findings suggest that APP faults in ICT-resistant tumors are not restricted to faults in peptide presentation to T lymphocytes (via B2M) but may also impact the presentation of tumor-associated lipid and glycolipid antigens via CD1d, which can impact antitumor responses of natural killer T cells (NKT). Adjuvant therapies that restore MHC-I and CD1d-mediated antigen presentation may unleash the response to ICT via NKT. Understanding CD1d expression faults locally and systemically may provide valuable prognostication information likely to impact how cancer is treated by optimally selecting patients for ICT and validating novel therapeutic targets for immunotherapy development. Citation Format: Carlos Rogerio Figueiredo. Lipid and glycolipid antigen presentation faults as a mechanism of resistance to immune checkpoint therapy in poorly immunogenic melanomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6635.