Impact of the BRAF V600E mutation on the immune microenvironment of CRC patients with MSI-high/dMMR status

In recent years, the presence of an MSI-high or dMMR status has become of particular clinical relevance in colorectal cancer (CRC) patients. However, a proportion of CRC patients with MSI-high status will also carry a BRAF V600E mutation. The study at hand examined the immune microenvironment of these CRC tumours and compared it to that of tumours in patients with a MSI-high status and wild-type BRAF. The results seem to indicate that both settings carry the same tumoral immune microenvironment. As such, this suggests that CRC patients with an MSI-high status may benefit from immune checkpoint inhibitors irrespective of their BRAF mutation status.

Previously, colorectal cancer (CRC) used to be treated as one disease. Nowadays, however, it is clear that CRC is made up of multiple subgroups of patients, with different oncogenic drivers. In this respect, patients with an MSI-high or dMMR status recently became of particular therapeutic relevance given their sensitivity to immune checkpoint inhibition (ICI). A proportion of patients with MSI-high CRC patients also carry a BRAF V600E mutation. In order to choose the best treatment strategy for these patients (i.e, ICI or anti-BRAF targeted therapy) , it is important to know the impact of this BRAF V600E mutation on the immune microenvironment. Therefore, this study examined the immune microenvironment of colorectal cancer patients who have MSI-high tumour as well as BRAF V600E mutation.

Study design

This retrospective review included a total of 459 CRC patients, all of whom were MSI-high or had a dMMR status. BRAF mutation status was known. Several immune markers of tumour immunogenicity in BRAF wild-type (BRAFwt ) vs. V600E-mutated (BRAFV 600E ) tumours were assessed, including tumour mutational burden (TMB), neoantigen tumour burden (NTB, ScanNeo), PD-L1 expression, immune infiltration, and canonical immuno-metabolomic pathways (82 geneset signatures).

Results

A total of 459 MSI-H/dMMR CRC tumours were analysed, after whch 123 (27%) were found to harbor a BRAF V600E mutation and 336 (73%) were BRAF wildtype. MSI-H/dMMR BRAF V600E tumors were more frequently observed in females than in males (69% vs. 55%; p= 0.01), and tended to be more prevalent in older patients. The analyses showed that patients with BRAF-mutated tumours had a similar NTB than patients who were BRAF wildtype, with an identical median of 15 mutations/Mb. The levels of CD4+ and CD8+ infiltrating T cells were also comparable between the groups. The groups did differ, however, looking at the proportion of infiltrating natural killer (NK) cells, which was significantly higher in the patients with BRAF-mutant than in wildtype tumours. The TH1 immune pathway also proved to be upregulated in BRAF-mutated tumours. Cancer stem cell pathways, including the Notch and WNT/Catenin signalling pathways, were significantly downregulated in BRAF-mutated tumours. By contrast, cyclin-dependent cell signalling as well as glycerophospholipid, galactose and nucleotide metabolism were significantly upregulated, pointing to “accelerated growth and metabolic reprograming.

Conclusions

Overall, the data suggest that BRAF mutant tumour MSI-high and BRAF wild-type mutant MSI-high CRC tumours carry a similar immune microenvironment. This suggests that both subgroups are equally likely to benefit from ICI treatment. The next question will be how RAS mutations play in this, and this is a topic of other studies that are already going on.

Reference

Salem M, Kopetz S, El-Refai S, et al. Impact of BRAF-V600E mutation on immunologic characteristics of the tumor microenvironment (TME) and associated genomic alterations in patients with microsatellite instability-high (MSI-H) or mismatch-repair–deficient (dMMR) colorectal cancer (CRC). Presented at ESMO WGCI 2022; Abstract LBA SO-34.