在腫瘤中高表達的基因，一般思路是，腫瘤中高表達，預(yù)后差，這類基因是促癌基因（A）；腫瘤中高表達，預(yù)后好，這類基因是抑癌基因（B）。但對于B類基因，在腫瘤中高表達且不利于腫瘤細胞存活，有點類似“自殺”，從進化角度看，不科學。腫瘤細胞為什么要去表達不利于自身生存的基因？我們以后再做討論。今天，我們主要談?wù)撨@種腫瘤中高表達，足夠好的情況！我們以下面這篇生信論文為例。

作者進行了差異表達驗證，也進行了生存的驗證。結(jié)論總結(jié)起來有三條：

1. HHLA2 was widely expressed in cancers at both the mRNA and protein levels. （HHLA2在腫瘤中廣泛表達）。

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在腎癌中高表達的驗證）。

3. HHLA2 was also positively correlated with survival rates in KIRC based on TCGA and clinical data. （HHLA2高表達預(yù)示腎癌生存期延長，既有數(shù)據(jù)庫驗證，也有臨床樣本驗證）。

差異表達分析，HHLA2在腫瘤中廣泛高表達。

生存分析，GEO+TCGA數(shù)據(jù)。

遺傳分析和表觀分析。

HHLA2與炎癥基因的相關(guān)分析

HHLA2與其他B7/CD28家族基因的相關(guān)分析。

HHLA2與CD8+ T細胞浸潤的相關(guān)分析。

討論部分最精彩

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.

這就需要我們對腫瘤免疫循環(huán)和免疫細胞遷移的動態(tài)過程有清晰的了解。腫瘤免疫循環(huán)，我們已經(jīng)分享太多次了，這次談?wù)?strong>免疫細胞遷移的過程。

1. 分化成熟：生命的起點

免疫細胞在特定器官中發(fā)育成熟：

• T 細胞：在胸腺中經(jīng)歷陽性/陰性選擇，獲得功能性受體（TCR）。

• B 細胞：在骨髓中完成基因重排，表達特異性BCR。

分化成熟的初始免疫細胞通過歸巢（Homing）遷移至次級淋巴器官（如淋巴結(jié)、脾臟），等待抗原識別：

• 趨化因子引導：如CCL19/CCL21通過結(jié)合CCR7受體，招募 T 細胞進入淋巴結(jié)。

• 黏附分子作用：L-選擇素（CD62L）介導細胞沿高內(nèi)皮微靜脈（HEVs）滾動，穩(wěn)定黏附后穿出血管。

在次級淋巴器官中，免疫細胞被抗原激活，分化為效應(yīng)細胞或記憶細胞：

• 樹突狀細胞（DCs）：攜帶抗原從外周組織進入血液（Intravasation），依賴整合素（如LFA-1）穿過血管壁。

• 效應(yīng)T/B細胞：通過淋巴管進入血液循環(huán)，開啟全身巡邏。

效應(yīng)細胞循炎癥信號遷移至感染或腫瘤部位，完成組織浸潤（Tissue Infiltration）：

• 趨化因子梯度：如CCL2招募單核細胞，CXCL10引導Th1細胞定向遷移。

• 黏附與穿透：ICAM-1/VCAM-1與整合素結(jié)合，Rho GTPases調(diào)控細胞變形，穿透血管內(nèi)皮進入組織。

免疫細胞在清除病原體后，通過離開組織（Egress）重返循環(huán)系統(tǒng)：

• S1P-S1PR信號軸：血液中高濃度S1P驅(qū)動記憶 T 細胞撤離炎癥部位。

• 趨化因子反向梯度：如CXCL12水平下降，促使細胞退出組織，回歸循環(huán)或遷移至淋巴結(jié)形成記憶。

分享這么多生信論文，感覺還是沒有跳出上面這張思維導圖。希望對大家有所幫助！