Jouanneau Emmanuel, Black Keith L, Veiga Lucia, Cordner Ryan, Goverdhana Shyam, Zhai Yuying, Zhang Xiao-xue, Panwar Akanksha, Mardiros Armen, Wang HongQiang, Gragg Ashley, Zandian Mandana, Irvin Dwain K, Wheeler Christopher J
Department of Neurosurgery, Cedars Sinai Medical Center, Advanced Health Sciences Pavilion, Maxine Dunitz Neurosurgical Institute, 127 S. San Vicente Blvd, Suite A8113, Los Angeles, CA, 90048, USA.
Cancer Immunol Immunother. 2014 Sep;63(9):911-24. doi: 10.1007/s00262-014-1559-2. Epub 2014 Jun 4.
Cancer vaccines reproducibly cure laboratory animals and reveal encouraging trends in brain tumor (glioma) patients. Identifying parameters governing beneficial vaccine-induced responses may lead to the improvement of glioma immunotherapies. CD103(+) CD8 T cells dominate post-vaccine responses in human glioma patients for unknown reasons, but may be related to recent thymic emigrant (RTE) status. Importantly, CD8 RTE metrics correlated with beneficial immune responses in vaccinated glioma patients.
We show by flow cytometry that murine and human CD103(+) CD8 T cells respond better than their CD103(-) counterparts to tumor peptide-MHC I (pMHC I) stimulation in vitro and to tumor antigens on gliomas in vivo.
Glioma responsive T cells from mice and humans both exhibited intrinsic de-sialylation-affecting CD8 beta. Modulation of CD8 T cell sialic acid with neuraminidase and ST3Gal-II revealed de-sialylation was necessary and sufficient for promiscuous binding to and stimulation by tumor pMHC I. Moreover, de-sialylated status was required for adoptive CD8 T cells and lymphocytes to decrease GL26 glioma invasiveness and increase host survival in vivo. Finally, increased tumor ST3Gal-II expression correlated with clinical vaccine failure in a meta-analysis of high-grade glioma patients.
Taken together, these findings suggest that de-sialylation of CD8 is required for hyper-responsiveness and beneficial anti-glioma activity by CD8 T cells. Because CD8 de-sialylation can be induced with exogenous enzymes (and appears particularly scarce on human T cells), it represents a promising target for clinical glioma vaccine improvement.
癌症疫苗可重复性地治愈实验动物，并在脑肿瘤（胶质瘤）患者中显示出令人鼓舞的趋势。确定有益的疫苗诱导反应的控制参数可能会改善胶质瘤免疫疗法。CD103(+) CD8 T细胞在人类胶质瘤患者的疫苗接种后反应中占主导地位，原因不明，但可能与近期胸腺迁出细胞（RTE）状态有关。重要的是，CD8 RTE指标与接种疫苗的胶质瘤患者的有益免疫反应相关。
我们通过流式细胞术表明，小鼠和人类的CD103(+) CD8 T细胞在体外对肿瘤肽-MHC I（pMHC I）刺激以及在体内对胶质瘤上的肿瘤抗原的反应优于其CD103(-)对应细胞。
来自小鼠和人类的胶质瘤反应性T细胞均表现出影响CD8β的内在去唾液酸化。用神经氨酸酶和ST3Gal-II调节CD8 T细胞唾液酸表明，去唾液酸化对于与肿瘤pMHC I的混杂结合和刺激是必要且充分的。此外，去唾液酸化状态是过继性CD8 T细胞和淋巴细胞在体内降低GL26胶质瘤侵袭性并提高宿主存活率所必需的。最后，在一项对高级别胶质瘤患者的荟萃分析中，肿瘤ST3Gal-II表达增加与临床疫苗失败相关。
综上所述，这些发现表明CD8的去唾液酸化是CD8 T细胞高反应性和有益的抗胶质瘤活性所必需的。由于CD8去唾液酸化可以用外源性酶诱导（并且在人类T细胞上似乎特别稀少），它代表了临床胶质瘤疫苗改进的一个有希望的靶点。
