Mapping Immune Correlates and Surfaceome Genes in BRAF Mutated Colorectal Cancers

Abstract

Despite the impressive results obtained with immunotherapy in several cancer types, a significant fraction of patients remains unresponsive to these treatments. In colorectal cancer (CRC), B-RafV600 mutations have been identified in 8–15% of the patients. In this work we interrogated a public dataset to explore the surfaceome of these tumors and found that several genes, such as GP2, CLDN18, AQP5, TM4SF4, NTSR1, VNN1, and CD109, were upregulated. By performing gene set enrichment analysis, we also identified a striking upregulation of genes (CD74, LAG3, HLA-DQB1, HLA-DRB5, HLA-DMA, HLA-DMB, HLA-DPB1, HLA-DRA, HLA-DOA, FCGR2B, HLA-DQA1, HLA-DRB1, and HLA-DPA1) associated with antigen processing and presentation via MHC class II. Likewise, we found a strong correlation between PD1 and PD(L)1 expression and the presence of genes encoding for proteins involved in antigen presentation such as CD74, HLA-DPA1, and LAG3. Furthermore, a similar association was observed for the presence of dendritic cells and macrophages. Finally, a low but positive relationship was observed between tumor mutational burden and neoantigen load. Our findings support the idea that a therapeutic strategy based on the targeting of PD(L)1 together with other receptors also involved in immuno-modulation, such as LAG3, could help to improve current treatments against BRAF-mutated CRC tumors.

Unraveling the Interplay of KRAS, NRAS, BRAF, and Micro-Satellite Instability in Non-Metastatic Colon Cancer: A Systematic Review

“…KRAS-mutated tumors exhibit decreased immune cell infiltration compared to KRAS wild-type tumors, whereas BRAF-mutated tumors, particularly concerning cytotoxic T cells and Th1 cells, demonstrate the opposite effect [55]. BRAF-mutated tumors have been associated not only with increased immune cell infiltration but also with the expression of immunotherapeutic targets [56]; however, the specific contributions of mutated BRAF and MSI to the immune response remain uncertain. Studies on immunotherapy in metastatic patients have revealed a potential benefit in the use of immune checkpoint inhibitors in MSI patients with BRAF mutations, despite the prognostic value of such mutations [55].…”