Surmann Eva-Maria, Voigt Anita Y, Michel Sara, Bauer Kathrin, Reuschenbach Miriam, Ferrone Soldano, von Knebel Doeberitz Magnus, Kloor Matthias
Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Cancer Immunol Immunother. 2015 Mar;64(3):357-66. doi: 10.1007/s00262-014-1638-4. Epub 2014 Dec 2.
Besides being expressed on professional antigen-presenting cells, HLA class II antigens are expressed on various tumors of non-lymphoid origin, including a subset of colorectal cancers (CRC). Information about the regulation of HLA class II antigen expression is important for a better understanding of their role in the interactions between tumor and immune cells. Whether lack of HLA class II antigen expression in tumors reflects the selective immune destruction of HLA class II antigen-expressing tumor cells is unknown. To address this question, we tested whether lack of HLA class II antigen expression in CRC was associated with immune cell infiltration. We selected microsatellite-unstable (MSI-H) CRC, because they show pronounced tumor antigen-specific immune responses and, in a subset of tumors, lack of HLA class II antigen expression due to mutations inactivating HLA class II-regulatory genes. We examined HLA class II antigen expression, mutations in regulatory genes, and CD4-positive T cell infiltration in 69 MSI-H CRC lesions. Mutations in RFX5, CIITA, and RFXAP were found in 13 (28.9%), 3 (6.7%), and 1 (2.2%) out of 45 HLA class II antigen-negative tumors. CD4-positive tumor-infiltrating lymphocyte counts were significantly higher in HLA class II antigen-negative tumors harboring mutations in HLA class II-regulatory genes (107.4 T cells per 0.25 mm(2)) compared to tumors without mutations (55.5 T cells per 0.25 mm(2), p = 0.008). Our results suggest that the outgrowth of tumor cells lacking HLA class II antigen expression due to mutations of regulatory genes is favored in an environment of dense CD4-positive T cell infiltration.
除了在专业抗原呈递细胞上表达外，HLA - II类抗原还在多种非淋巴源性肿瘤上表达，包括一部分结直肠癌（CRC）。了解HLA - II类抗原表达的调控信息对于更好地理解它们在肿瘤与免疫细胞相互作用中的作用至关重要。肿瘤中HLA - II类抗原表达的缺失是否反映了表达HLA - II类抗原的肿瘤细胞的选择性免疫破坏尚不清楚。为了解决这个问题，我们测试了CRC中HLA - II类抗原表达的缺失是否与免疫细胞浸润有关。我们选择了微卫星不稳定（MSI - H）的CRC，因为它们显示出明显的肿瘤抗原特异性免疫反应，并且在一部分肿瘤中，由于HLA - II类调控基因的突变而缺乏HLA - II类抗原表达。我们检查了69个MSI - H CRC病变中的HLA - II类抗原表达、调控基因突变和CD4阳性T细胞浸润情况。在45个HLA - II类抗原阴性肿瘤中，分别有13个（28.9%）、3个（6.7%）和1个（2.2%）检测到RFX5、CIITA和RFXAP基因的突变。与无突变的肿瘤（每0.25平方毫米55.5个T细胞，p = 0.008）相比，在携带HLA - II类调控基因突变的HLA - II类抗原阴性肿瘤中，CD4阳性肿瘤浸润淋巴细胞计数显著更高（每0.25平方毫米107.4个T细胞）。我们的结果表明，在密集的CD4阳性T细胞浸润环境中，由于调控基因突变而缺乏HLA - II类抗原表达的肿瘤细胞的生长更有利。
