Poor clinical outcome in metastatic melanoma is associated with a microRNA-modulated immunosuppressive tumor microenvironment

Abstract

Background: Interaction 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. Methods: Interested 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. Results: The 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 micro-RNAs 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. Conclusion: Our results underscore the impact of tumor-microenvironment interactions on disease outcomes and reveal potential non-invasive biomarkers of prognosis and treatment response.

Development of an immune-related gene pairs index for the prognosis analysis of metastatic melanoma

“…These studies indicated that the IRGs in IRGPI played an important role in the occurrence and development of cancers, suggesting that our prognostic model would have good prospect and prognostic value in metastatic melanoma. The infiltration of immune cells in the tumor microenvironment played an important role in the progression of cancers, and it was also reported in metastatic melanoma in a wide variety studies 27,35 . Therefore, we calculated the score of 29 immune cells infiltration in each sample using ssGSEA to further explore the correlation between tumor microenvironment immune cells infiltration and IRGPI.…”

Extracellular vesicle-mediated crosstalk between melanoma and the immune system: Impact on tumor progression and therapy response

“…This may reflect antitumor responses that are mediated by EVs or be a consequence of the release of tumor‐induced EVs by immune cells aiming to boost tumor progression. The latter is difficult to untangle due to the high complex network of gene regulation encompassed in the TME 5,23,26 . In breast tumors, M2 Mϕ‐derived exosomes sustain tumor cell dormancy 27 while glioma‐derived EVs inhibit T cell activation and PBMC migration 28 .…”

“…The latter is difficult to untangle due to the high complex network of gene regulation encompassed in the TME. 5,23,26 In breast tumors, M2 M -derived exosomes sustain tumor cell dormancy 27 30 Zhu and collaborators 31 analyzed the contents of NK-derived exosomes using NK-92 cells and identified higher levels of perforin and FasL in these vesicles than in the cell itself ( Fig. 1).…”

“…In addition to malignant cells, the complexity of a melanoma comprises a mix of skin‐resident cells 3 and recruited cells 4 . This heterogeneous system varies in its cellular composition among patients and among individual tumors 5,6 and the interplay between these components may exert important effects on tumor development and progression. Single‐cell RNA sequencing analysis has allowed better characterization of the TME by identifying its main cell types and phenotypes and deciphering their individual roles in tumor progression and therapy response 6‐8 .…”

“…6,8 Mesenchymal stem cells (MSCs) can also be recruited from bone marrow to the TME. 9 These various cell types communicate with each other, delivering important pro-and antitumor signals, including cytotoxic and phenotype-changing signals, 5 justifying a better understanding of how the crosstalk between melanoma and the TME cells hinders or triggers tumor development and progression.…”