高表达预后好的基因，如何讨论

在肿瘤中高表达的基因，一般思路是，肿瘤中高表达，预后差，这类基因是促癌基因（A）；肿瘤中高表达，预后好，这类基因是抑癌基因（B）。但对于B类基因，在肿瘤中高表达且不利于肿瘤细胞存活，有点类似“自杀”，从进化角度看，不科学。肿瘤细胞为什么要去表达不利于自身生存的基因？我们以后再做讨论。今天，我们主要谈论这种肿瘤中高表达，足够好的情况！我们以下面这篇生信论文为例。

作者进行了差异表达验证，也进行了生存的验证。结论总结起来有三条：

1. HHLA2 was widely expressed in cancers at both the mRNA and protein levels. （HHLA2在肿瘤中广泛表达）。

2. In KIRC, HHLA2 levels were significantly higher in tumor tissues than in matched normal samples, as evidenced by both TCGA and IHC data.（HHLA2在肾癌中高表达的验证）。

3. HHLA2 was also positively correlated with survival rates in KIRC based on TCGA and clinical data. （HHLA2高表达预示肾癌生存期延长，既有数据库验证，也有临床样本验证）。

差异表达分析，HHLA2在肿瘤中广泛高表达。

生存分析，GEO+TCGA数据。

遗传分析和表观分析。

HHLA2与炎症基因的相关分析

HHLA2与其他B7/CD28家族基因的相关分析。

HHLA2与CD8+ T细胞浸润的相关分析。

讨论部分最精彩

Several studies have reported that HHLA2 is a negative indicator in colon, lung and pancreatic cancers (Cheng et al., 2017; Zhu and Dong, 2018; Yan et al., 2019). The poor prognostic value of HHLA2 was also reported in clear cell RCC (Chen D. et al., 2019; Chen L. et al., 2019). However, increased HHLA2 expression was associated with better post-surgical prognosis in pancreatic and ampullary cancers when using a different anti-HHLA2 antibody clone for IHC (Boor et al., 2020). Herein, we also observed that HHLA2 is a positive predictor in KIRC.

These opposing functions highlight that the expression and distribution of HHLA2 and its receptors may determine the reactions and immune responses in tumor microenvironment, further affecting the prognosis. The different datasets or cohorts used in these studies may also lead to the contradictory prognostic value of HHLA2 in cancers. A similar phenomenon was observed for PD-L1 expression and its prognostic significance in various tumors. In colorectal, breast, and ovary cancers, PD-L1 expression represents a better outcome (Darb-Esfahani et al., 2016; Li et al., 2016; Kitano et al., 2017), whereas worse prognostic outcomes were observed in gastrointestinal, esophageal, and pancreatic cancers as well as glioma and hepatocellular carcinoma.

这就需要我们对肿瘤免疫循环和免疫细胞迁移的动态过程有清晰的了解。肿瘤免疫循环，我们已经分享太多次了，这次谈谈免疫细胞迁移的过程。

1. 分化成熟：生命的起点

免疫细胞在特定器官中发育成熟：

• T 细胞：在胸腺中经历阳性/阴性选择，获得功能性受体（TCR）。

• B 细胞：在骨髓中完成基因重排，表达特异性BCR。

分化成熟的初始免疫细胞通过归巢（Homing）迁移至次级淋巴器官（如淋巴结、脾脏），等待抗原识别：

• 趋化因子引导：如CCL19/CCL21通过结合CCR7受体，招募 T 细胞进入淋巴结。

• 黏附分子作用：L-选择素（CD62L）介导细胞沿高内皮微静脉（HEVs）滚动，稳定黏附后穿出血管。

在次级淋巴器官中，免疫细胞被抗原激活，分化为效应细胞或记忆细胞：

• 树突状细胞（DCs）：携带抗原从外周组织进入血液（Intravasation），依赖整合素（如LFA-1）穿过血管壁。

• 效应T/B细胞：通过淋巴管进入血液循环，开启全身巡逻。

效应细胞循炎症信号迁移至感染或肿瘤部位，完成组织浸润（Tissue Infiltration）：

• 趋化因子梯度：如CCL2招募单核细胞，CXCL10引导Th1细胞定向迁移。

• 黏附与穿透：ICAM-1/VCAM-1与整合素结合，Rho GTPases调控细胞变形，穿透血管内皮进入组织。

免疫细胞在清除病原体后，通过离开组织（Egress）重返循环系统：

• S1P-S1PR信号轴：血液中高浓度S1P驱动记忆 T 细胞撤离炎症部位。

• 趋化因子反向梯度：如CXCL12水平下降，促使细胞退出组织，回归循环或迁移至淋巴结形成记忆。

分享这么多生信论文，感觉还是没有跳出上面这张思维导图。希望对大家有所帮助！