Version 1
: Received: 8 March 2024 / Approved: 11 March 2024 / Online: 12 March 2024 (13:48:58 CET)
How to cite:
Mentucci, F.M.; Romero Nuñez, E.A.; Ercole, A.; Silvetti, V.; Dal Col, J.; Lamberti, M.J. Exploring the Role of BRAFV600E in Melanoma Immune Microenvironment and Its Impact on Modulating the IFN-1 Pathway for Therapeutic Response. Preprints2024, 2024030668. https://doi.org/10.20944/preprints202403.0668.v1
Mentucci, F.M.; Romero Nuñez, E.A.; Ercole, A.; Silvetti, V.; Dal Col, J.; Lamberti, M.J. Exploring the Role of BRAFV600E in Melanoma Immune Microenvironment and Its Impact on Modulating the IFN-1 Pathway for Therapeutic Response. Preprints 2024, 2024030668. https://doi.org/10.20944/preprints202403.0668.v1
Mentucci, F.M.; Romero Nuñez, E.A.; Ercole, A.; Silvetti, V.; Dal Col, J.; Lamberti, M.J. Exploring the Role of BRAFV600E in Melanoma Immune Microenvironment and Its Impact on Modulating the IFN-1 Pathway for Therapeutic Response. Preprints2024, 2024030668. https://doi.org/10.20944/preprints202403.0668.v1
APA Style
Mentucci, F.M., Romero Nuñez, E.A., Ercole, A., Silvetti, V., Dal Col, J., & Lamberti, M.J. (2024). Exploring the Role of BRAFV600E in Melanoma Immune Microenvironment and Its Impact on Modulating the IFN-1 Pathway for Therapeutic Response. Preprints. https://doi.org/10.20944/preprints202403.0668.v1
Chicago/Turabian Style
Mentucci, F.M., Jessica Dal Col and María Julia Lamberti. 2024 "Exploring the Role of BRAFV600E in Melanoma Immune Microenvironment and Its Impact on Modulating the IFN-1 Pathway for Therapeutic Response" Preprints. https://doi.org/10.20944/preprints202403.0668.v1
Abstract
The BRAFV600E mutation, found in approximately 50% of melanoma cases, is associated with aggressive tumor behavior and poor prognosis. This study aimed to assess its impact 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, emphasizing 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.
Keywords
BRAFV600E mutation; IFN-1 pathway; melanoma
Subject
Biology and Life Sciences, Immunology and Microbiology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
