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  • A multi-omics analysis of metastatic melanoma identifies a germinal center-like tumor microenvironment in HLA-DR-positive tumor areas [Elektronski vir]
    Gadeyne, Laura ...
    The emergence of immune checkpoint inhibitors has dramatically changed the therapeutic landscape for patients with advanced melanoma. However, relatively low response rates and a high incidence of ... severe immune-related adverse events have prompted the search for predictive biomarkers. A positive predictive value has been attributed to the aberrant expression of Human Leukocyte Antigen-DR (HLA-DR) by melanoma cells, but it remains unknown why this is the case. In this study, we have examined the microenvironment of HLA-DR positive metastatic melanoma samples using a multi-omics approach. First, using spatial, single-cell mapping by multiplexed immunohistochemistry, we found that the microenvironment of HLA-DR positive melanoma regions was enriched by professional antigen presenting cells, including classical dendritic cells and macrophages, while a more general cytotoxic T cell exhaustion phenotype was present in these regions. In parallel, transcriptomic analysis on micro dissected tissue from HLA-DR positive and HLA-DR negative areas showed increased IFN% signaling, enhanced leukocyte adhesion and mononuclear cell proliferation in HLA-DR positive areas. Finally, multiplexed cytokine profiling identified an increased expression of germinal center cytokines CXCL12, CXCL13 and CCL19 in HLA-DR positive metastatic lesions, which, together with IFN% and IL4 could serve as biomarkers to discriminate tumor samples containing HLA-DR overexpressing tumor cells from HLA-DR negative samples. Overall, this suggests that HLA-DR positive areas in melanoma attract the anti-tumor immune cell infiltration by creating a dystrophic germinal center-like microenvironment where an enhanced antigen presentation leads to an exhausted microenvironment, nevertheless representing a fertile ground for a better efficacy of anti-PD-1 inhibitors due to simultaneous higher levels of PD-1 in the immune cells and PD-L1 in the HLA-DR positive melanoma cells.
    Vir: Frontiers in oncology [Elektronski vir]. - ISSN 2234-943X (Vol. 11, March 2021, str. 1-16)
    Vrsta gradiva - e-članek
    Leto - 2021
    Jezik - angleški
    COBISS.SI-ID - 61117443

    Povezava(-e):

    https://www.frontiersin.org/articles/10.3389/fonc.2021.636057/full
    DOI

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