Abstract
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 IFNγ 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 IFNγ 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.
Highlights
Primary Cutaneous Melanoma (PCM) is characterized by an aggressive course including metastatic spread directly proportional to the depth of invasion of the tumor cells into the skin [1]
The main goal of this study was aimed at defining the composition and characteristics of the tumor microenvironment of Human Leukocyte Antigen-DR (HLA-DR)+ metastatic melanoma samples compared to HLA-DR- negative areas/tumors at single cell and spatial level
We observed that ~7% of the identified MelanA +/S100B+ melanoma cells were positive for HLA-DR (13497 HLA-DR+ vs 177829 HLA-DR- cells)
Summary
Primary Cutaneous Melanoma (PCM) is characterized by an aggressive course including metastatic spread directly proportional to the depth of invasion of the tumor cells into the skin (typically defined as the Breslow thickness) [1]. PCM is characterized by one of the highest somatic mutation rates [2], from which only a minority are driver mutations, while rest are passenger mutations that do not play a role in tumor development or progression. This high tumor mutational burden (TMB) can translate into a high amount of neo-antigens available for antigen recognition by the immune system, a feature that has been attributed to the strong immunogenicity of melanoma and the clinical effect of immunotherapy in these patients. Despite the plethora of different markers, none of those mentioned can predict response with acceptable accuracy and none of them have been prospectively evaluated in the context of a clinical trial which is why they have not found their way to daily clinical practice
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