O'Connell Patrick, Hyslop Sean, Blake Maja K, Godbehere Sarah, Amalfitano Andrea, Aldhamen Yasser A
Department of Microbiology and Molecular Genetics, College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824; and.
Department of Pediatrics, College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824.
J Immunol. 2021 Jan 1;206(1):193-205. doi: 10.4049/jimmunol.2000300. Epub 2020 Dec 7.
T cell exhaustion represents one of the most pervasive strategies tumors employ to circumvent the immune system. Although repetitive, cognate TCR signaling is recognized as the primary driving force behind this phenomenon, and it remains unknown what other forces drive T cell exhaustion in the tumor microenvironment (TME). In this study, we show that activation of the self-ligand SLAMF7 immune receptor on T cells induced STAT1 and STAT3 phosphorylation, expression of multiple inhibitory receptors, and transcription factors associated with T cell exhaustion. Analysis of The Cancer Genome Atlas revealed that SLAMF7 transcript levels were strongly correlated with various inhibitory receptors and that high SLAMF7 expression was indicative of poor survival in clear cell renal cell carcinoma (ccRCC). Targeted reanalysis of a CyTOF dataset, which profiled the TME in 73 ccRCC patients, revealed cell-type-specific SLAMF7 expression patterns, strong correlations between exhausted T cells and SLAMF7 tumor-associated macrophages (TAMs), and a unique subset of SLAMF7CD38 TAMs. These SLAMF7CD38 TAMs showed the strongest correlations with exhausted T cells and were an independent prognostic factor in ccRCC. Confirmatory ex vivo coculture studies validated that SLAMF7-SLAMF7 interactions between murine TAMs and CD8 T cells induce expression of multiple inhibitory receptors. Finally, mice lacking SLAMF7 show restricted growth of B16-F10 tumors, and CD8 T cells from these mice express less PD-1 and TOX and exhibited an impaired ability to progress through the exhaustion developmental trajectory to terminal exhaustion. These findings suggest that SLAMF7 might play an important role in modulating T cell function in the TME.
T细胞耗竭是肿瘤规避免疫系统最普遍采用的策略之一。尽管重复性同源TCR信号传导被认为是这一现象背后的主要驱动力，但肿瘤微环境（TME）中驱动T细胞耗竭的其他因素仍不清楚。在本研究中，我们发现T细胞上的自身配体信号淋巴细胞激活分子家族7（SLAMF7）免疫受体激活可诱导信号转导和转录激活因子1（STAT1）和信号转导和转录激活因子3（STAT3）磷酸化、多种抑制性受体的表达以及与T细胞耗竭相关的转录因子。对癌症基因组图谱的分析显示，SLAMF7转录水平与各种抑制性受体密切相关，并且高SLAMF7表达表明透明细胞肾细胞癌（ccRCC）患者生存率较低。对一个质谱流式细胞术（CyTOF）数据集进行针对性重新分析，该数据集对73例ccRCC患者的TME进行了分析，结果揭示了细胞类型特异性的SLAMF7表达模式、耗竭T细胞与SLAMF7肿瘤相关巨噬细胞（TAM）之间的强相关性，以及一个独特的SLAMF7⁺CD38⁺ TAM亚群。这些SLAMF7⁺CD38⁺ TAM与耗竭T细胞的相关性最强，并且是ccRCC的一个独立预后因素。体外共培养验证性研究证实，小鼠TAM与CD8⁺ T细胞之间的SLAMF7 - SLAMF7相互作用可诱导多种抑制性受体的表达。最后，缺乏SLAMF7的小鼠显示B16 - F10肿瘤生长受限，并且这些小鼠的CD8⁺ T细胞表达较少的程序性死亡受体1（PD - 1）和毒力诱导因子（TOX），并且在通过耗竭发育轨迹发展至终末耗竭方面能力受损。这些发现表明，SLAMF7可能在调节TME中的T细胞功能方面发挥重要作用。
