Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.
Proc Natl Acad Sci U S A. 2011 Jun 28;108(26):10656-61. doi: 10.1073/pnas.1100354108. Epub 2011 Jun 13.
HLA-E is a nonclassical HLA class I molecule, which differs from classical HLA molecules by its nonpolymorphic, conserved nature. Expression and function of HLA-E in normal tissues and solid tumors is not fully understood. We investigated HLA-E protein expression on tissue sections of 420 ovarian and cervical cancers and found equal or higher levels than normal counterpart epithelia in 80% of the tumors. Expression was strongly associated with components of the antigen presentation pathway, e.g., transporter associated with antigen processing (TAP), endoplasmic reticulum aminopeptide (ERAP), β2 microglobulin (β2m), HLA classes I and II, and for ovarian cancer with tumor infiltrating CD8(+) T lymphocytes (CTLs). This association argues against the idea that HLA-E would compensate for the loss of classical HLA in tumors. In situ detection of HLA-E interacting receptors revealed a very low infiltrate of natural killer (NK) cells, but up to 50% of intraepithelial CTLs expressed the inhibiting CD94/NKG2A receptor. In cervical cancer, HLA-E expression did not alter the prognostic effect of CTLs, most likely due to very high infiltrating CTL numbers in this virus-induced tumor. Overall survival of ovarian cancer patients, however, was strongly influenced by HLA-E, because the beneficial effect of high CTL infiltration was completely neutralized in the subpopulation with strong HLA-E expression. Interestingly, these results indicate that CTL infiltration in ovarian cancer is associated with better survival only when HLA-E expression is low and that intratumoral CTLs are inhibited by CD94/NKG2A receptors on CTLs in the tumor microenvironment.
HLA-E 是一种非经典的 HLA I 类分子，与经典 HLA 分子不同，其具有非多态性和保守性。正常组织和实体肿瘤中 HLA-E 的表达和功能尚未完全了解。我们研究了 420 例卵巢癌和宫颈癌组织切片中的 HLA-E 蛋白表达，发现 80%的肿瘤中 HLA-E 的表达水平与正常上皮相当或更高。表达与抗原呈递途径的成分密切相关，例如抗原处理转运体（TAP）、内质网氨肽酶（ERAP）、β2 微球蛋白（β2m）、HLA I 类和 II 类，以及卵巢癌中的肿瘤浸润性 CD8+T 淋巴细胞（CTL）。这种关联表明 HLA-E 不会补偿肿瘤中经典 HLA 的缺失。HLA-E 相互作用受体的原位检测显示 NK 细胞浸润非常低，但高达 50%的上皮内 CTL 表达抑制性 CD94/NKG2A 受体。在宫颈癌中，HLA-E 表达并未改变 CTL 的预后效应，这很可能是由于这种病毒诱导的肿瘤中浸润 CTL 的数量非常高。然而，卵巢癌患者的总生存率受到 HLA-E 的强烈影响，因为高 CTL 浸润的有益效应在 HLA-E 表达强烈的亚群中完全被中和。有趣的是，这些结果表明，只有在 HLA-E 表达水平较低时，卵巢癌中的 CTL 浸润才与更好的生存相关，并且肿瘤微环境中的 CTL 上的 CD94/NKG2A 受体抑制了肿瘤内的 CTL。
