High Expression of Interferon Pathway Genes CXCL10 and STAT2 Is Associated with Activated T-Cell Signature and Better Outcome of Oral Cancer Patients

Abstract

To improve the survival rate of cancer patients, biomarkers for both early diagnosis and patient stratification for appropriate therapeutics play crucial roles in precision oncology. Investigation of altered gene expression and the relevant molecular pathways in cancer cells are helpful for discovering such biomarkers. In this study, we explore the potential prognostic biomarkers for oral cancer patients through systematically analyzing five oral cancer transcriptomic data sets (TCGA, GSE23558, GSE30784, GSE37991, and GSE138206). Gene Set Enrichment Analysis (GSEA) was individually applied to each data set and the upregulated Hallmark molecular pathways of each data set were intersected to generate 13 common pathways including interferon-α/γ pathways. Among the 5 oral cancer data sets, 43 interferon pathway genes were commonly upregulated and 17 genes exhibited prognostic values in TCGA cohort. After validating in another oral cancer cohort (GSE65858), high expressions of C-X-C motif chemokine ligand 10 (CXCL10) and Signal transducer and activator of transcription 2 (STAT2) were confirmed to be good prognostic biomarkers. GSEA of oral cancers stratified by CXCL10/STAT2 expression showed that activation of T-cell pathways and increased tumor infiltration scores of Type 1 T helper (Th1) and CD8+ T cells were associated with high CXCL10/STAT2 expression. These results suggest that high CXCL10/STAT2 expression can predict a favorable outcome in oral cancer patients.

STAT2 Controls Colorectal Tumorigenesis and Resistance to Anti-Cancer Drugs

“…Accumulating evidence suggests that STAT2 may be a critical player in the tumor microenvironment [10] as it was shown to be able to either promote [29] or block [30,47] tumorigenesis. Very recent data indicated that STAT2 controlled the level of intestinal inflammation in different mouse models of experimental colitis.…”

Oncogenic STAT Transcription Factors as Targets for Cancer Therapy: Innovative Strategies and Clinical Translation

“…In contrast, STAT2-sustained late IFN-I signaling promotes the expression of pro-inflammatory mediators and genes involved in chemoresistance and immunosuppression that confer tumor cell survival and disease progression [102]. Overexpression of STAT2 has been associated with outcome changes in human skin cancers, head and neck, kidney, lung, ovary, and endometrium [103][104][105][106].…”

The duality of STAT2 mediated type I interferon signaling in the tumor microenvironment and chemoresistance

“…IFN-I-induced STAT2 mediated responses -as part of the ISGF3 complex-are classically regarded as antiproliferative, antiangiogenic, and proapoptotic. Yet emerging studies find STAT2 to be overexpressed in several human cancers of the skin, head and neck, kidney, lung, ovary, and endometrium and associated with either better or worse outcome [ 8 – 12 ]. Additionally, persistent STAT2 activity can cause hyperinflammation and be detrimental to the host [ 13 , 14 ].…”

“…It is worth noting that CXCL10 is an important chemokine in antitumor immunity, as it aids in the recruitment of T cells and natural killer cells to the tumor site with recent studies reporting that CXCL10 is required for the therapeutic efficacy of immune checkpoint blockade [ 41 – 44 ]. Furthermore, high expression of CXCL10 and STAT2 has been linked to increased survival among patients suffering from oral cancer due to greater activation of T cells [ 12 ].…”