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Study Probes Immune Context Differences in BRAF-Mutant, Wild-Type Melanoma


Investigators said these differences might help explain why some patients have better outcomes than others with combination immune checkpoint blockades.

Patients with BRAF-mutant melanoma have significantly different immune microenvironments compared with patients with BRAF wild-type melanoma, according to a new study published in Journal for ImmunoTherapy of Cancer.

The findings could lead to a better understanding of why certain therapies work or do not work in patients with different types of melanoma, the study investigators noted.

About 4 in 10 melanomas have BRAF mutations, the majority of which are BRAF V600 mutations characterized by the substitution of glutamic acid for valine at amino acid 600, they wrote. In patients with BRAF V600 mutations, the combination of BRAF and MEK inhibition often boosts survival, but the investigators said the benefits of the therapy tend to be short lived, with a progression-free survival of only about 12 months.

The authors said immune checkpoint inhibitors (ICIs) such as pembrolizumab (Keytruda) and nivolumab (Opdivo) have shown strong 5-year survival rates, and the combination of nivolumab with ipilimumab (Yervoy) has exceeded 52%.

However, there is mounting evidence that BRAF status may be an important factor in predicting treatment success. Patients with a BRAF mutation had a 5-year survival rate of 60% with nivolumab plus ipilimumab, while those without had a 48% 5-year survival rate. A separate study found that an interferon γ gene expression signature was a solid prognostic tool for predicting the success of BRAF and MEK inhibitors.

“These data further emphasize the critical role of the immune response in determining the clinical benefit from not only ICIs but also targeted therapy,” the authors wrote. “Thus, an in-depth characterization of the treatment-naive immune context in melanoma with BRAF mutations is needed.”

The investigators decided to undertake a systematic analysis of the immune context of treatment-naive cases of melanoma, with and without the BRAF mutation. They first used single-cell RNA sequencing to characterize the immune context patients, finding that patients with BRAF-mutant melanoma had significantly reduced CD8+ T-cell infiltration and a reduction in macrophages. However, these patients also had increased B cells, natural killer cells, and natural killer T cells.

Next, the investigators used bulk RNA sequencing, using a skin cutaneous melanoma cohort. In this analysis, the investigators found elevated levels of CD4+ T cells in patients with BRAF-mutant tumors compared with those with BRAF-wild type cancers. This was true both in patients with a primary cancer and in those with metastatic disease. Patients with BRAF-mutant metastatic melanoma had more B cells but less CD8+ T-cell infiltration vs patients with BRAF wild-type melanoma.

Additional testing using flow cytometry and multiplex immunohistochemistry techniques also showed BRAF-mutant melanoma metastases were enriched for CD4+ T cells and B cells but had a decrease in CD8+ T cells. The authors said B cells appeared to be associated with improved survival in patients with BRAF-mutant samples, but Th2 cells were associated with longer survival in BRAF wild-type cases.

Collectively, they said these data show BRAF-mutant melanoma has a distinct immune context compared with its wild-type counterpart, characterized by increased CD4+ T cells and B cells in the tumor microenvironment, along with a decrease in CD8+ T cells.

The study investigators concluded that the findings suggest additional study is warranted to better understand how the immune-context differences affect outcomes in combination immune checkpoint blockades.

“This study characterizing cell type compositions provides an opportunity to better understand the tumor microenvironment of BRAF-mutant and BRAF [wild-type] melanoma samples and to tailor management for patients with melanoma,” they wrote.


Wang M, Zadeh S, Pizzolla A, et al. Characterization of the treatment-naive immune microenvironment in melanoma with BRAF mutation. J Immunother Cancer. Published online April 2022. doi:10.1136/jitc-2021-004095

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