Dong Jianfeng, Cheng Lijun, Zhao Minchao, Pan Xiangfeng, Feng Zhiqiang, Wang Dawei
Department of Stomatology, The Third Hospital of Hebei Medical University, Shijiazhuang, P.R. China.
Tumour Biol. 2017 May;39(5):1010428317701651. doi: 10.1177/1010428317701651.
Oropharyngeal head and neck squamous cell carcinoma is a common malignant tumor in the oral cavity. High-risk human papillomavirus 16 infection is a major cause of oropharyngeal head and neck squamous cell carcinoma development. Strong antitumor immune responses, especially CD8 T cell responses, are thought to be essential to effective cancer treatment and are associated with better prognosis in oropharyngeal head and neck squamous cell carcinoma. In this study, we examined the role of the Tim-3/Gal-9 pathway in oropharyngeal head and neck squamous cell carcinoma patients. We found that Gal-9 expression by CD4 T cells was increased in human papillomavirus-positive oropharyngeal head and neck squamous cell carcinoma patients, but not in human papillomavirus-negative oropharyngeal head and neck squamous cell carcinoma patients. Increased Gal-9 secretion by CD4 T cells presented multiple immunosuppressive effects. Coculturing monocytes with high Gal-9-expressing CD4 T cells resulted in the expansion of Tim-3 monocytes, which suppressed interferon gamma production by activated CD8 T cells. Subsequently, total monocytes incubated with exogenous Gal-9, or high Gal-9-expressing CD4 T cells, suppressed the expression of interferon gamma by CD8 T cells. Exogenous Gal-9 and high Gal-9-expressing CD4 T cells also suppressed the secretion of both interleukin 10 and interleukin 12 by monocytes. These effects are Tim-3/Gal-9-dependent because blocking Tim-3 and/or Gal-9 could enhance the support of CD8 T cell interferon gamma production and the interleukin 10 and interleukin 12 secretion by monocytes. Together, these data suggest that the high Tim-3 expression in monocytes could be utilized by tumor-promoting Gal-9 expression on CD4 T cells. Immunotherapy in human papillomavirus-positive oropharyngeal head and neck squamous cell carcinoma patients therefore faces an additional challenge posed by Tim-3 and Gal-9 and likely requires the blockade of these molecules.
口咽头颈鳞状细胞癌是口腔中常见的恶性肿瘤。高危型人乳头瘤病毒16感染是口咽头颈鳞状细胞癌发生的主要原因。强大的抗肿瘤免疫反应，尤其是CD8 T细胞反应，被认为对有效的癌症治疗至关重要，并且与口咽头颈鳞状细胞癌的较好预后相关。在本研究中，我们检测了Tim-3/Gal-9通路在口咽头颈鳞状细胞癌患者中的作用。我们发现，在人乳头瘤病毒阳性的口咽头颈鳞状细胞癌患者中，CD4 T细胞的Gal-9表达增加，但在人乳头瘤病毒阴性的口咽头颈鳞状细胞癌患者中未增加。CD4 T细胞分泌的Gal-9增加呈现出多种免疫抑制作用。将单核细胞与高表达Gal-9的CD4 T细胞共培养导致Tim-3单核细胞扩增，这抑制了活化的CD8 T细胞产生干扰素γ。随后，用外源性Gal-9或高表达Gal-9的CD4 T细胞孵育的总单核细胞抑制了CD8 T细胞干扰素γ的表达。外源性Gal-9和高表达Gal-9的CD4 T细胞也抑制了单核细胞分泌白细胞介素10和白细胞介素12。这些作用是Tim-3/Gal-9依赖性的，因为阻断Tim-3和/或Gal-9可以增强对CD8 T细胞干扰素γ产生的支持以及单核细胞分泌白细胞介素10和白细胞介素12。总之，这些数据表明，单核细胞中高表达的Tim-3可被CD4 T细胞上促进肿瘤的Gal-9表达所利用。因此，人乳头瘤病毒阳性的口咽头颈鳞状细胞癌患者的免疫治疗面临Tim-3和Gal-9带来的额外挑战，可能需要阻断这些分子。
