Mapping Immune Correlates and Surfaceome Genes in BRAF Mutated Colorectal Cancers

Simple Summary The identification of novel therapeutic strategies for Colorectal Cancer (CRC) patients with BRAF mutations is mandatory, since most of the current treatments against this tumor type, including novel compounds, show limited efficacy. In this article, we describe upregulated proteins in the surface of cells within the tumor that can be used as targets to specifically guide novel treatments. In addition, we also observed that the transcriptomic profile matches with antigen presenting cells, such as dendritic cells and macrophages having antigen processing and presentation of exogenous peptide antigen via MHC class II as main molecular function, favoring an immunoreactive microenvironment. Therefore, the combination of anti PD(L)1, together with other co-inhibitor receptors from the ones presented in this manuscript, should be explored to treat BRAF mutated CRC patients. 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.

Automated summary

This study describes a novel therapeutic strategy for treating colorectal cancer (CRC) patients with BRAF mutations. By identifying upregulated proteins on the surface of tumor cells as treatment targets and observing the transcriptional profile associated with antigen presenting cells, it is suggested that a combination of anti PD(L)1 with other co-inhibitor receptors can be explored for treating BRAF-mutated CRC patients.