CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Prognostic values of B7-H3, B7-H4, and HHLA2 expression in human pancreatic cancer tissues based on mIHC and spatial distribution analysis.
Prognostic values of B7-H3, B7-H4, and HHLA2 expression in human pancreatic cancer tissues based on mIHC and spatial distribution analysis.
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我们的研究表明 B7-H3、B7-H4 和 HHLA2 在人 PC 组织中的表达和预后价值存在差异，并证明由 CD68+ TAMs 表达的这些共刺激分子可作为 PC 患者预后预测的重要生物标志物。此外，这些结果支持将这些标志物的评估作为抗 PC 免疫治疗的重要候选靶点。
胰腺癌（PC）是最恶性的实体肿瘤之一，其5年生存率仍然很低。尽管免疫治疗在一些临床试验中取得了一定的疗效，但此类治疗仍显示出较低的缓解率和总体缓解率。因此，迫切需要剖析肿瘤微环境并优化针对该恶性肿瘤的免疫治疗策略。
采用多色免疫组织化学检测方法，我们研究了63例PC组织芯片中B7-H3、B7-H4、HHLA2、CD8和CD68的表达情况。此外，我们还分析了这些分子的免疫定位特征、临床相关性及预后价值。
B7-H3、B7-H4和HHLA2的表达可在细胞角蛋白染色阳性（CK+）的癌上皮细胞、CD68+肿瘤相关巨噬细胞（TAMs），甚至其他被定义为CK-CD8-CD68-的细胞中检测到。肿瘤细胞中B7-H3的高表达可预测PC患者更好的生存。肿瘤细胞中B7-H3与HHLA2的表达呈正相关，而肿瘤细胞中B7-H4与HHLA2的表达呈负相关。CD68+TAMs中B7-H3与B7-H4或HHLA2的表达呈正相关，但B7-H4与HHLA2之间无相关性。肿瘤浸润CD8+T细胞联合CD68+TAMs可作为PC患者术后预后的重要预测指标。CD68+TAMs中B7-H3或HHLA2的高表达可作为PC患者预后较差的重要预测指标。在联合分析中，CD68+TAMs上B7-H3低B7-H4低、B7-H3低HHLA2低或B7-H4低HHLA2低的患者相比其他亚群可能具有更好的术后预后。
Pancreatic cancer (PC) is one of the most malignant solid tumors and its 5-year survival rate remains poor. Although immunotherapy has achieved certain therapeutic efficacy in some clinical trials, such treatment still shows low responses and overall remission rate. Therefore, it is urgently necessary to dissect the tumor microenvironment and optimize the immunotherapeutic strategies against this malignancy.
Using the multi-color immunohistochemistry assay, we investigated the expressions of B7-H3, B7-H4, HHLA2, CD8, and CD68 in 63 cases of PC tissues in a tissue microarray. Moreover, we analyzed immunolocalization features, clinical associations and prognostic values of these molecules.
The expressions of B7-H3, B7-H4, and HHLA2 could be detected in cytokeratin staining positive (CK + ) cancer epithelial cells, CD68 + tumor-associated macrophages (TAMs), and even other cells defined as CK - CD8 - CD68 - . Higher expression of B7-H3 in tumor cells could predict a better survival of the PC patients. A positive correlation was found between the expressions of B7-H3 and HHLA2 in tumor cells, while there was a negative correlation between the expressions of B7-H4 and HHLA2 in tumor cells. A positive correlation was found between the expressions of B7-H3 and B7-H4 or HHLA2 in CD68 + TAMs, but not B7-H4 and HHLA2. Tumor-infiltrating CD8 + T cells in combination with CD68 + TAMs could serve as an important predictor for the postoperative prognosis of PC patients. Higher expression of B7-H3, or HHLA2 in CD68 + TAMs could serve as an important predictor for poorer prognosis of PC patients. Patients with B7-H3 low B7-H4 low , B7-H3 low HHLA2 low , or B7-H4 low HHLA2 low on CD68 + TAMs could have a better postoperative prognosis compared with the other sub-populations in the combinational analysis.
Taken together, our study indicated variable expressions and prognostic values of B7-H3, B7-H4, and HHLA2, in human PC tissues, and demonstrated that these co-stimulator molecules expressed by CD68 + TAMs could be used as important bio-markers for the prognostic prediction of PC patients. Moreover, these results supported that the evaluation of these markers could be used as essential candidate targets for immunotherapy against PC.
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