Impact of Genomic Mutation on Melanoma Immune Microenvironment and IFN-1 Pathway-Driven Therapeutic Responses

Author:

Mentucci Fátima María1,Romero Nuñez Elisa Ayelén1,Ercole Agustina1,Silvetti Valentina1,Dal Col Jessica2ORCID,Lamberti María Julia1ORCID

Affiliation:

1. Departamento de Biología Molecular, INBIAS, Universidad Nacional de Río Cuarto, Río Cuarto X5800BIA, Argentina

2. Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana, University of Salerno, 84081 Baronissi, Italy

Abstract

The BRAFV600E mutation, found in approximately 50% of melanoma cases, plays a crucial role in the activation of the MAPK/ERK signaling pathway, which promotes tumor cell proliferation. This study aimed to evaluate its impact on the melanoma immune microenvironment and therapeutic responses, particularly focusing on immunogenic cell death (ICD), a pivotal cytotoxic process triggering anti-tumor immune responses. Through comprehensive in silico analysis of the Cancer Genome Atlas data, we explored the association between the BRAFV600E mutation, immune subtype dynamics, and tumor mutation burden (TMB). Our findings revealed that the mutation correlated with a lower TMB, indicating a reduced generation of immunogenic neoantigens. Investigation into immune subtypes reveals an exacerbation of immunosuppression mechanisms in BRAFV600E-mutated tumors. To assess the response to ICD inducers, including doxorubicin and Me-ALA-based photodynamic therapy (PDT), compared to the non-ICD inducer cisplatin, we used distinct melanoma cell lines with wild-type BRAF (SK-MEL-2) and BRAFV600E mutation (SK-MEL-28, A375). We demonstrated a differential response to PDT between the WT and BRAFV600E cell lines. Further transcriptomic analysis revealed upregulation of IFNAR1, IFNAR2, and CXCL10 genes associated with the BRAFV600E mutation, suggesting their involvement in ICD. Using a gene reporter assay, we showed that PDT robustly activated the IFN-1 pathway through cGAS-STING signaling. Collectively, our results underscore the complex interplay between the BRAFV600E mutation and immune responses, suggesting a putative correlation between tumors carrying the mutation and their responsiveness to therapies inducing the IFN-1 pathway, such as the ICD inducer PDT, possibly mediated by the elevated expression of IFNAR1/2 receptors

Funder

Florencio Fiorini para Investigación en Ciencias Biomédicas

Publisher

MDPI AG

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