Abstract
The tumor microenvironment (TME), including infiltrated immune cells, is known to play an important role in tumor growth; however, the mechanisms underlying tumor immunogenicity have not been fully elucidated. Here, we discovered an unexpected role for the transcription factor SIX1 in regulating the tumor immune microenvironment. Based on analyses of patient datasets, we found that SIX1 was upregulated in human tumor tissues and that its expression levels were negatively correlated with immune cell infiltration in the TME and the overall survival rates of cancer patients. Deletion of Six1 in cancer cells significantly reduced tumor growth in an immune-dependent manner with enhanced antitumor immunity in the TME. Mechanistically, SIX1 was required for the expression of multiple collagen genes via the TGFBR2-dependent Smad2/3 activation pathway, and collagen deposition in the TME hampered immune cell infiltration and activation. Thus, our study uncovers a crucial role for SIX1 in modulating tumor immunogenicity and provides proof-of-concept evidence for targeting SIX1 in cancer immunotherapy.
Highlights
Cancer is a global public health problem, and tumors develop in response to changes in both cancer cells and the tumor microenvironment (TME)
High expression of Six1 negatively correlates with immune cell infiltration in the TME and patient survival rates In the course of investigating the molecular mechanisms responsible for regulating the TME through aberrant gene expression in cancer cells, we found that sine oculis homeobox 1 (SIX1) was highly expressed in the cancerous tissues of most tumors (Fig. S1A)
The prognostic efficiency of SIX1 expression was assessed by time-dependent ROC curves, which showed that the area under the curve (AUC) values were 0.621 (1 year), 0.637 (3 years), and 0.679 (5 years) (Fig. 1C), indicating that SIX1 expression has good predictive value for the overall mortality of SARC patients
Summary
Cancer is a global public health problem, and tumors develop in response to changes in both cancer cells and the tumor microenvironment (TME). Alterations in gene expression profiles and genomic mutations are necessary for normal cells to transform into cancer cells. Cancer cells within the TME can regulate the composition of the TME. The TME plays crucial roles in tumor growth, therapeutic response, and patient outcomes [1]. There is growing evidence showing that altering gene expression in cancer cells can directly or indirectly affect the TME [2]. The transcription factor sine oculis homeobox 1 (SIX1), as a critical regulator of organogenesis, is highly expressed during embryonic development but is rarely expressed in normal human adult tissues [3]. The role of SIX1 in tumor growth and its associated mechanisms involved in regulating the TME remain to be elucidated
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