While studies have indicated that squamous cell carcinoma of the head and neck (HNSCC) is associated with immune suppression, these studies did not analyze the immune response at the dysplastic stage. The present study utilized a mouse model of 4-nitroquinoline 1-oxide-induced oral carcinogenesis to examine the alterations in immune phenotype at the premalignant and malignant stages of HNSCC. Cervical lymph nodes of HNSCC-bearing mice were found to contain a greater number of cells, including a greater number of conventional (Tconv) and regulatory (Treg) T cells, compared to cervical lymph nodes of control and premalignant lesion-bearing mice, though the Tconv cells appear to be less proliferative and the Treg cells appear to be less suppressive at the HNSCC stage. Premalignant lesion-bearing mouse lymph nodes consist of a greater percentage of Tconv cells expressing markers for activation, memory, and exhaustion compared to both control and HNSCC-bearing mice. Also, lymph nodes’ cells from both premalignant lesion-bearing and HNSCC-bearing mice include increased levels of Th1, Tc1, and Th17 cells, with no differences in levels of Th2 cells, compared to control mice. The data show that while there is the expected increase in immunosuppressive Tregs in lymph nodes when HNSCC is present, there is also an unexpected increase in immune populations usually associated with a beneficial antitumor response, including Tconv cells and Th1 and Tc1 cells. In addition, the results demonstrate that the premalignant stage of HNSCC development is associated with a robust immune response involving an increase in inflammatory Th1, Tc1, and Th17 cells.
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.
Head and neck squamous cell carcinoma (HNSCC) is marked by immunosuppression, a state in which the established tumor escapes immune attack. However, the impact of the premalignant and tumor microenvironments on immune reactivity has yet to be elucidated. The purpose of this study was to determine how soluble mediators from cells established from carcinogen-induced oral premalignant lesions and HNSCC modulate immune cell cytokine production. It was found that premalignant cells secrete significantly increased levels of G-CSF, RANTES, MCP-1, and PGE2 compared to HNSCC cells. Splenocytes incubated with premalignant supernatant secreted significantly increased levels of Th1-, Th2-, and Th17-associated cytokines compared to splenocytes incubated with HNSCC supernatant. These studies demonstrate that whereas the premalignant microenvironment elicits proinflammatory cytokine production, the tumor microenvironment is significantly less immune stimulatory and may contribute to immunosuppression in established HNSCC.
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