Abstract
BackgroundInteraction between malignant cells and immune cells that reside within the tumor microenvironment (TME) modulate different aspects of tumor development and progression. Recent works showed the importance of miRNA-containing extracellular vesicles in this crosstalk.MethodsInterested in understanding the interplay between melanoma and immune-related TME cells, we characterized the TCGA’s metastatic melanoma samples according to their tumor microenvironment profiles, HLA-I neoepitopes, transcriptome profile and classified them into three groups. Moreover, we combined our results with melanoma single-cell gene expression and public miRNA data to better characterize the regulatory network of circulating miRNAs and their targets related to immune evasion and microenvironment response.ResultsThe group associated with a worse prognosis showed phenotypic characteristics that favor immune evasion, including a strong signature of suppressor cells and less stable neoantigen:HLA-I complexes. Conversely, the group with better prognosis was marked by enrichment in lymphocyte and MHC signatures. By analyzing publicly available melanoma single-cell RNA and microvesicle microRNAs sequencing data we identified circulating microRNAs potentially involved in the crosstalk between tumor and TME cells. Candidate miRNA/target gene pairs with previously reported roles in tumor progression and immune escape mechanisms were further investigated and demonstrated to impact patient’s overall survival not only in melanoma but across different tumor types.ConclusionOur results underscore the impact of tumor-microenvironment interactions on disease outcomes and reveal potential non-invasive biomarkers of prognosis and treatment response.
Highlights
Interaction between malignant cells and immune cells that reside within the tumor microenvironment (TME) modulate different aspects of tumor development and progression
Clinical outcome of melanoma patients is impacted by the immune‐related tumor microenvironment In order to characterize human metastatic melanoma samples according to their associated immune phenotypes, we inferred the tumor microenvironment (TME)-associated immune cell populations [10] of 164 metastatic samples from The Cancer Genome Atlas (TCGA) database (Additional file 1: Table S1)
According to the TME predictions, G1 samples are enriched in naïve, memory and plasma B cells, and depleted in resting natural killer (NK) cells; G2 samples are enriched in CD8+ T cells, monocytes, and macrophages M1; and G3 samples are enriched in M0 macrophages and depleted in plasma cells, CD8+ T cells, memory activated CD4+ T cells, follicular T helper cells, activated NK cells, monocytes, and resting dendritic cells (p ≤ 0.05, Mann–Whitney test—MW) (Fig. 1a and Additional file 1: Figure S1A)
Summary
Interaction between malignant cells and immune cells that reside within the tumor microenvironment (TME) modulate different aspects of tumor development and progression. Numerous studies have confirmed that tumor progression and recurrence are shaped by the tumor microenvironment (TME) [3, 4] besides the genetic changes inherent to the cancer cells During melanomagenesis, both tumor cell proliferation and apoptosis are shaped by the activity of immune cells [5]. Both tumor cell proliferation and apoptosis are shaped by the activity of immune cells [5] In this process called immunoediting [6], the features that suppress the cytotoxic immune infiltrate and promote tumor survival are positively selected. The understanding of these mechanisms has been crucial for treatment improvement and for the development of new immunotherapy strategies. The observed variation in treatment efficacy has been related to heterogeneity in the composition of immune cells among individual tumors as well as the tumor mutation burden and expression of immune checkpoint molecules, but these factors alone cannot accurately predict a successful outcome of patients treated with immune checkpoint blockade [8, 9]
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