探查PD-L1表現量對與EB病毒相關的多種癌症的影響

Abstract

EB病毒（Epstein-Barr virus）是一種廣泛感染人群並可能有致癌能力的人類皰疹病毒，因其主要感染人類之B細胞以及上皮細胞，所以與多種B淋巴細胞癌以及上皮細胞癌具有顯著的相關性。本實驗室先前研究顯示，B細胞之免疫抑制分子，細胞程式死亡-配體1（PD-L1）的表現量會受到EB病毒感染而顯著提升。因此，本研究蒐集與EB病毒相關的多種癌症，包括瀰漫性大B細胞淋巴瘤、經典霍奇金氏淋巴瘤、鼻咽癌以及胃癌之cDNA微陣列以及生存資訊資料集，旨在探查PD-L1表現量對這些癌症患者生存率是否具有影響。首先，本研究確認，EB病毒與胃癌之PD-L1的高表現量相關。本研究進而通過生存分析發現，PD-L1在多種可能與EB病毒相關的癌症之資料集中，均不會影響患者的總生存期。並且在部分胃癌資料集GSE84437中，PD-L1的較高表現量與患者較長的總生存期呈正相關。由於PD-L1在腫瘤免疫微環境中，不僅表現於腫瘤細胞上，還表現在以免疫細胞為主的腫瘤浸潤細胞中，因此本研究所探討的腫瘤免疫微環境總PD-L1表現量包括腫瘤細胞及腫瘤浸潤細胞的表現。在本研究使用的所有可能與EB病毒相關的癌症之資料集中，腫瘤免疫微環境的總PD-L1表現量，均與具有可能腫瘤抑制作用的M1型巨噬細胞之浸潤量呈正相關，表示可能為患者較好的預後因子。此外，本研究也發現，總PD-L1的表現量，也與腫瘤浸潤CD8+ T細胞之PD-L1配體PD-1（細胞程式死亡-1）的表現量呈正相關，表示可能為患者較差的預後因子。以上結果表明，總PD-L1在多種與EB病毒相關之癌症中，總PD-L1同時與較好和較差的預後因子顯著相關。同時本研究也發現，EB病毒影響並降低了總PD-L1表現量與M1型巨噬細胞浸潤量之相關性，證實EB病毒可能上調腫瘤細胞之PD-L1表現量。綜合以上研究結果，本研究發現，腫瘤免疫微環境之總PD-L1表現量在多種與EB病毒相關之癌症中，可能同時與較好和較差的預後因素有關。亦即，總PD-L1表現量可作為一把雙刃劍，其表現量對與EB病毒相關的多種癌症可能同時具有兩種看似相反的影響。

Epstein-Barr virus (EBV) is a widely infective human herpesvirus with oncogenic potential. The virus primarily infects human B cells and epithelial cells, and its infection is significantly associated with various B-cell lymphomas and carcinomas. Previous cDNA microarray data performed in our laboratory have shown that the expression of programmed death-ligand 1 (PD-L1), an immune checkpoint molecule in B cells, is significantly upregulated upon EBV infection. Therefore, this study collected cDNA microarray and survival information datasets related to various EBV-associated cancers, including diffuse large B-cell lymphoma, classical Hodgkin lymphoma, nasopharyngeal carcinoma, and gastric carcinoma, with the aim of investigating the influence of PD-L1 expression. Firstly, this study confirmed the association between EBV and high PD-L1 expression in gastric carcinoma, a clinical report. Furthermore, survival analysis revealed that PD-L1 did not shorten the overall survival rate of patients in the datasets of several cancers possibly related to EBV. In a subset of gastric carcinoma datasets GSE84437, higher PD-L1 expression was associated with longer overall survival. The PD-L1 expression investigated in this study refers to the total PD-L1 expression in the tumor immune microenvironment since PD-L1 is expressed not only on tumor cells but also on tumor-infiltrating immune cells in the tumor immune microenvironment. Analysis of tumor-infiltrating immune cells showed that in all the datasets of possible EBV-associated cancers used in this study, the total PD-L1 expression in the tumor immune microenvironment was positively correlated with the infiltration of M1 macrophages, which have tumor-suppressive effects, possibly as a good prognostic factor. The total PD-L1 expression was also positively correlated with the expression of PD-1 (programmed death-1), the ligand of PD-L1, on tumor-infiltrating CD8+ T cells, possibly as a poor prognostic factor. These results indicated that the total PD-L1 expression is significantly associated with both better and worse prognostic factors in various EBV-associated cancers. Furthermore, this study hinted that EBV may influence the correlation between total PD-L1 expression and the amounts of infiltrated M1 macrophages, suggesting that EBV upregulates PD-L1 expression on tumor cells. In conclusion, this study discovered that the total PD-L1 expression in the tumor immune microenvironment may be simultaneously associated with both better and worse prognostic factors in various EBV-related cancers. In other words, the expression of total PD-L1 may have dual effects, exerting opposite influences on multiple EBV-associated cancers.