Human melanomas and ovarian cancers overexpressing mechanical barrier molecule genes lack immune signatures and have increased patient mortality risk

Abstract

We have identified eight genes whose expression in human melanoma metastases and ovarian cancers is associated with a lack of Th1 immune signatures. They encode molecules with mechanical barrier function in the skin and other normal tissues and include filaggrin (FLG), tumor-associated calcium signal transducer 2 (TACSTD2), and six desmosomal proteins (DST, DSC3, DSP, PPL, PKP3, and JUP). This association has been validated in an independent series of 114 melanoma metastases. In these, DST expression alone is sufficient to identify melanomas without immune signatures, while FLG and the other six putative barrier molecules are overexpressed in a different subset of melanomas lacking immune signatures. Similar associations have been identified in a set of 186 ovarian cancers. RNA-seq data from 471 melanomas and 307 ovarian cancers in the TCGA database further support these findings and also reveal that overexpression of barrier molecules is strongly associated with early patient mortality for melanoma (p = 0.0002) and for ovarian cancer (p < 0.01). Interestingly, this association persists for FLG for melanoma (p = 0.012) and ovarian cancer (p = 0.006), whereas DST overexpression is negatively associated with CD8+ gene expression, but not with patient survival. Thus, overexpression of FLG or DST identifies two distinct patient populations with low immune cell infiltration in these cancers, but with different prognostic implications for each. These data raise the possibility that molecules with mechanical barrier function in skin and other tissues may be used by cancer cells to protect them from immune cell infiltration and immune-mediated destruction.

Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab

“…Some of these newly identified gene products may be considered as candidate targets for future combination immunotherapy trials. Most patients with PD had minimal immune response on-therapy, and differential gene analysis did not identify a dominant or single method of tumor-intrinsic immune evasion, suggesting an immune ignorance or immune exclusion mechanism rather than an adaptive resistance mechanism (Salerno et al, 2016; Spranger et al, 2013) (Figure 4B). In contrast, many patients with SD appeared to have modest immune response induction, suggesting that an adaptive mechanism of resistance may have a more important role in these patients (Taube et al, 2012; Taube et al, 2015).…”

High‐risk Stage III colon cancer patients identified by a novel five‐gene mutational signature are characterized by upregulation of IL‐23A and gut bacterial translocation of the tumor microenvironment

“…SMAD4 is an essential gene that regulates cell proliferation through the TGF-β signaling pathway. 21 COL6A3 and LRP1B are involved in cancer metastasis through the regulation of cell adhesion. 31 SMAD4 loss alters bone morphogenic protein signaling to promote CRC cell metastasis.…”

“…MSI-H, hypermutated or Stage IIIA colon cancer cases were not included in this analysis. 21 COL6A3 and LRP1B are involved in cell adhesion and tight junction disruption. Forty-six downregulated and 39 upregulated genes were detected in patients of high-risk groups (Supporting Information Table S8).…”

“…MUC16 and FLG are both known mechanical barrier genes. 21 COL6A3 and LRP1B are involved in cell adhesion and tight junction disruption. 22 Significantly changes of extracellular related genes may be the consequence of loss function of these four genes.…”

The MAPK hypothesis: immune-regulatory effects of MAPK-pathway genetic dysregulations and implications for breast cancer immunotherapy

“…These traits include the genomic activation of the WNT/β-catenin [38] and PI3K-AKT pathways [39], and the expression of transcripts encoding for proteins with mechanical barrier functions such as filaggrin and desmosomal proteins [40,41].…”