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
BRAFV600E突变存在于约50%的黑色素瘤病例中，在激活MAPK/ERK信号通路、促进肿瘤细胞增殖方面起着关键作用。本研究旨在评估该突变对黑色素瘤免疫微环境及治疗反应的影响，特别聚焦于免疫原性细胞死亡（ICD）——一种触发抗肿瘤免疫反应的关键细胞毒性过程。通过对癌症基因组图谱数据进行全面的生物信息学分析，我们探讨了BRAFV600E突变与免疫亚型动态及肿瘤突变负荷（TMB）之间的关联。研究发现，该突变与较低的TMB相关，表明免疫原性新抗原生成减少。对免疫亚型的研究显示，BRAFV600E突变肿瘤中的免疫抑制机制更为显著。为评估ICD诱导剂（包括多柔比星和基于Me-ALA的光动力疗法）与非ICD诱导剂顺铂的治疗反应差异，我们采用具有野生型BRAF（SK-MEL-2）和BRAFV600E突变（SK-MEL-28、A375）的不同黑色素瘤细胞系进行研究。实验证实野生型与BRAFV600E突变细胞系对光动力疗法的反应存在差异。进一步的转录组分析显示，BRAFV600E突变与IFNAR1、IFNAR2和CXCL10基因的上调相关，提示这些基因可能参与ICD过程。通过基因报告实验，我们证明光动力疗法通过cGAS-STING信号通路显著激活了IFN-1通路。综上所述，我们的研究结果揭示了BRAFV600E突变与免疫反应之间复杂的相互作用，表明携带该突变的肿瘤可能通过IFNAR1/2受体表达升高，增强对IFN-1通路诱导疗法（如ICD诱导剂光动力疗法）的治疗敏感性。
肿瘤(癌症)患者之家