Abstract
While head and neck squamous cell carcinomas (HNSCC) are associated with profound immune suppression, less is known about the immunological milieu of premalignant oral lesions. The present study shows dynamic shifts in the immune milieu within premalignant oral lesions and when they have progressed to HNSCC. Specifically, this study showed that the premalignant lesion environment consists of inflammatory mediators and IL-17, but this inflammatory phenotype declines when premalignant oral lesions have progressed to HNSCC. The cytokine profiles of human tissues did not correspond with plasma cytokine profiles. A murine carcinogen-induced premalignant lesion model that progresses to HNSCC was used to examine cytokine profiles released from tissues as well as regional lymph nodes. As in human tissues, murine premalignant lesions and regional lymph nodes released high levels of inflammatory cytokines and, very prominently, IL-17. Also similar to human tissues, release of inflammatory cytokines declined in HNSCC tissues of mice and in the regional lymph nodes of mice with HNSCC. Studies focusing on IL-17 showed that mediators from premalignant lesions stimulated normal spleen cells to produce increased levels of IL-17, while mediators from HNSCC were less stimulatory toward IL-17 production. IL-17 production by Th17-skewed CD4+ cells was strongly inhibited by normal oral epithelium as well as HNSCC. In contrast, premalignant lesion-derived mediators further increased IL-17 production by Th17-skewed cells. The stimulation of IL-17 production by premalignant lesions was dependent on IL-23, which premalignant lesions released in higher amounts than control tissues or HNSCC. HNSCC tissues instead produced increased levels of TGF-β compared to premalignant lesions, and skewed normal spleen cells toward the Treg phenotype. This skewing was blocked by supplementation with IL-23. These studies suggest IL-23 to be a significant contributor to the inflammatory IL-17 phenotype in premalignant oral lesions and suggest the decline in IL-23 in HNSCC leads to a decline in Th17 cells.
Highlights
Despite advances in diagnosis and treatment, the 5-year survival rates for patients with head and neck squamous cell carcinoma (HNSCC) have remained at only 60% [1]
The current study showed the dynamic shifts in the immune milieu within premalignant oral lesions and when they have progressed to HNSCC, with the premalignant lesion environment consisting of inflammatory mediators and IL-17, and a sharp decline in this inflammatory environment in HNSCC
Th1 and inflammatory cytokine levels were measured in homogenates of premalignant oral lesions that were surgically excised from patients and compared to levels in normal oral tissues and HNSCC
Summary
Despite advances in diagnosis and treatment, the 5-year survival rates for patients with head and neck squamous cell carcinoma (HNSCC) have remained at only 60% [1]. Our prior study in a carcinogen-induced oral premalignant lesion mouse model showed an increased percentage of conventional T-cells and cells expressing markers for activation, memory, and exhaustion compared to either healthy control or HNSCC-bearing mice [7]. These studies showed the premalignant stage to be associated with robust immune reactivity involving increases in inflammatory, Th1/Tc1 and Th17 cells in the regional lymph nodes, while the number of Treg cells increased prominently in mice with HNSCC. Similar to our studies with the mouse premalignant oral lesion model, Th17 levels have been shown to be increased in patients with gastric and ovarian cancers, with a shift from Th17 to Treg cells in advanced disease [8,9]. Studies in a mouse pancreatic cancer model showed that tumor overexpression of IL-6 increases induction of Th17 cells, reduces development of cancer and improves mouse survival [17]
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