| The head and neck squamous cell carcinoma (HNSCC) microenvironment was recently shown to contain various types of bacteria, and exhibits chronic inflammation, including monocyte-lineage cells. High numbers of CD68-1 monocyte-lineage cells in HNSCC were reported to directly correlate with progression of HNSCC, but the mechanisms underlying this correlation are not known. In response to microbial products, monocyte-lineage cells produce factors, such as interleukin (IL)-6, that may support cancer cell survival and thus promote cancer progression. I hypothesized that (1) the interactions between HNSCC cells and monocytes affect monocyte phenotype and function, (2) the interactions between HNSCC cells, monocytes and microbial products lead to the production of cancer-supportive factors, such as IL-6, and (3) the produced factors, in turn, activate pro-survival factors in HNSCC cells. My studies using co-cultures of keratinocytes and HNSCC cell lines with freshly isolated monocytes from normal donors revealed that the monocytes became CD16+, reminiscent of the CD16 + "pro-inflammatory" peripheral blood monocytes. Further, HNSCC cells strongly suppressed monocyte ability to produce destructive tumor necrosis factor (TNF)-alpha in response to bacterial lipopolysaccharide (LPS), while cancer-supportive IL-6 production in response to LPS was preserved or enhanced. Correspondingly, there was preferential production of Type 2 and proangiogenic factors with little, if any production of Type 1 factors in LPS-stimulated co-cultures, and the soluble factors strongly and rapidly induced activation of Signal Transducer and Activator of Transcription (STAT)3 in HNSCC cells, a pro-survival factor known to be important in HNSCC and other cancers. In fibroblasts and osteosarcoma cells, STAT3 was shown to antagonize the effects of STAT1, which is a key player in interferon (IFN)-gamma-mediated Type 1 anti-tumor immune response. As predicted, the induced factors protected HNSCC cells from the toxic effects of IFN-gamma, which correlated with the activation of STAT3. These results are significant, because they show a path by which contamination of HNSCC microenvironment with microbial products may support HNSCC cell survival and thus lead to cancer progression. |
