Abstract
BackgroundHuman microsatellite-stable (MSS) colorectal cancers (CRCs) are immunologically “cold” tumour subtypes characterized by reduced immune cytotoxicity. The molecular linkages between immune-resistance and human MSS CRC is not clear.MethodsWe used transcriptome profiling, in silico analysis, immunohistochemistry, western blot, RT-qPCR and immunofluorescence staining to characterize novel CRC immune biomarkers. The effects of selective antagonists were tested by in vitro assays of long term viability and analysis of kinase active forms using anti-phospho antibodies.ResultsWe identified the lymphocyte antigen 6 complex, locus G6D (LY6G6D) as significantly overexpressed (around 15-fold) in CRC when compared with its relatively low expression in other human solid tumours. LY6G6D up-regulation was predominant in MSS CRCs characterized by an enrichment of immune suppressive regulatory T-cells and a limited repertoire of PD-1/PD-L1 immune checkpoint receptors. Coexpression of LY6G6D and CD15 increases the risk of metastatic relapse in response to therapy. Both JAK-STAT5 and RAS-MEK-ERK cascades act in concert as key regulators of LY6G6D and Fucosyltransferase 4 (FUT4), which direct CD15-mediated immune-resistance. Momelotinib, an inhibitor of JAK1/JAK2, consistently abrogated the STAT5/LY6G6D axis in vitro, sensitizing MSS cancer cells with an intact JAK-STAT signaling, to efficiently respond to trametinib, a MEK inhibitor used in clinical setting. Notably, colon cancer cells can evade JAK2/JAK1-targeted therapy by a reversible shift of the RAS-MEK-ERK pathway activity, which explains the treatment failure of JAK1/2 inhibitors in refractory CRC.ConclusionsCombined targeting of STAT5 and MAPK pathways has superior therapeutic effects on immune resistance. In addition, the new identified LY6G6D antigen is a promising molecular target for human MSS CRC.
Highlights
Human microsatellite-stable (MSS) colorectal cancers (CRCs) are immunologically “cold” tumour subtypes characterized by reduced immune cytotoxicity
It is well known that microsatellite instability (MSI) and mismatch repair (MMR) defects can lead to DNA hypermutation and the production of immunogenic neo-peptides, recognized by antigen-specific tumour infiltrating lymphocytes, which is counterbalanced by the upregulation of multiple immune checkpoint molecules [8,9,10]
Lymphocyte antigen 6 complex (LY6G6D) was highly expressed in colorectal cancer compared to normal tissues, whereas Fucosyltransferase 4 (FUT4) expression levels, tended to be significantly higher in CRC than in normal mucosa in two out of three databases (Fig. 1b)
Summary
Human microsatellite-stable (MSS) colorectal cancers (CRCs) are immunologically “cold” tumour subtypes characterized by reduced immune cytotoxicity. In CRC patients, only a modest clinical effect of MAPK inhibitors has been reported In this context, studies have shown that CD15, called Lewisx antigen, synthetized by Fucosyltransferase 4 (FUT4), is induced by the RAFMEK-ERK signaling pathway, and colon cancers that are FUT4+/CD15+ seem to exhibit significant alteration of the systemic immune surveillance and resistance to the anti-EGFR agents (cetuximab) [5]. It is well known that microsatellite instability (MSI) and mismatch repair (MMR) defects can lead to DNA hypermutation and the production of immunogenic neo-peptides, recognized by antigen-specific tumour infiltrating lymphocytes, which is counterbalanced by the upregulation of multiple immune checkpoint molecules [8,9,10] These tumours are characterized by a predominant type of T helper cells (Th) with Th1 phenotype (Th1), which potentiate the lytic function of cytotoxic effector T cells present in the tumor microenvironment, activating IFNγ, IL-15 and JAK (Janus kinase)/STAT (signal transducer and activator of transcription) pathways [11, 12]. Tumours defective in MMR machinery represent only 5% of all metastatic colorectal cancers and they are more recognized by the immune system [13]
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