Jlassi Aida, Rejaibi Rim, Manai Maroua, Sahraoui Ghada, Guerfali Fatma Zahra, Charfi Lamia, Mezlini Amel, Manai Mohamed, Mrad Karima, Doghri Raoudha
Research Laboratory of Precision Medicine/Personalized Medicine and Oncology Investigation Salah Azaiz Institute, Tunis, Tunisia.
Department of Biology, Mycology, Pathologies and Biomarkers Laboratory, Faculty of Sciences of Tunis, University of Tunis El Manar, Ariana, Tunisia.
Front Oncol. 2024 Apr 3;14:1352053. doi: 10.3389/fonc.2024.1352053. eCollection 2024.
Immunotherapy by blocking immune checkpoints programmed death/ligand (PD1/PDL1) and cytotoxic T-lymphocyte-associated protein 4(CTLA4) has emerged as new therapeutic targets in cancer. However, their efficacy has been limited due to resistance. A new- checkpoint V-domain Ig-containing suppressor of T cell activation (VISTA) has appeared, but the use of its inhibition effect in combination with antibodies targeting PDL1/PD1and CTLA4 has not been reported in ovarian cancer.
In this study, we investigated the expressions of VISTA, CTLA4, and PDL1 using immunohistochemistry (IHC)on 135 Formalin-Fixed Paraffin-Embedded (FFPE)tissue samples of High-grade serous carcinoma (HGSOC). VISTA, CTLA4, PDL1, PD1, CD8, CD4, and FOXP3 mRNA extracted from 429 patients with ovarian cancer in the Cancer Genome Atlas (TCGA) database was included as a validation cohort. Correlations between these checkpoints, tumor-infiltrating- lymphocytes (TILs), and survival were analyzed.
CTLA4 was detectable in 87.3% of samples, VISTA in 64.7%, PD1 in 56.7%, and PDL1 in 48.1%. PDL1 was the only tested protein associated with an advanced stage (=0.05). VISTA was associated with PDL1, PD1, and CTLA4 expressions (=0.005, =0.001, =0.008, respectively), consistent with mRNA level analysis from the TCGA database. Univariate analyses showed only VISTA expression (=0.04) correlated with overall survival (OS). Multivariate analyses showed that VISTA expression (=0.01) and the coexpression of VISTA/CTLA4/PD1 (=0.05) were associated with better OS independently of the clinicopathological features. Kaplan-Meier analysis showed that the coexpression of the VISTA/CTLA4/PDL1 and VISTA/CTLA4/PD1 checkpoints on tumor cells (TCs)were associated with OS (p=0.02 and <0.001; respectively). VISTA/CTLA4/PD1 in TCs and CD4/CD8TILswere associated with better 2-yer OS. This correlation may refer to the role of VISTA as a receptor in the TCs and not in the immune cells. Thus, targeting combination therapy blocking VISTA, CTLA4, and PD1 could be a novel and attractive strategy for HGSOC treatment, considering the ambivalent role of VISTA in the HGSOC tumor cells.
通过阻断免疫检查点程序性死亡/配体（PD1/PDL1）和细胞毒性T淋巴细胞相关蛋白4（CTLA4）进行免疫治疗已成为癌症治疗的新靶点。然而，由于耐药性，它们的疗效受到限制。一种新的检查点——含V结构域免疫球蛋白的T细胞激活抑制因子（VISTA）已被发现，但在卵巢癌中，尚未有关于其抑制作用与靶向PDL1/PD1和CTLA4抗体联合使用的报道。
在本研究中，我们采用免疫组织化学（IHC）方法检测了135例高级别浆液性癌（HGSOC）福尔马林固定石蜡包埋（FFPE）组织样本中VISTA、CTLA4和PDL1的表达。从癌症基因组图谱（TCGA）数据库中429例卵巢癌患者提取的VISTA、CTLA4、PDL1、PD1、CD8、CD4和FOXP3 mRNA作为验证队列。分析了这些检查点、肿瘤浸润淋巴细胞（TILs）与生存率之间的相关性。
87.3%的样本中可检测到CTLA4，64.7%的样本中可检测到VISTA，56.7%的样本中可检测到PD1，48.1%的样本中可检测到PDL1。PDL1是唯一与晚期相关的检测蛋白（P=0.05）。VISTA与PDL1、PD1和CTLA4的表达相关（分别为P=0.005、P=0.001、P=0.008）,这与TCGA数据库中的mRNA水平分析结果一致。单因素分析显示，只有VISTA表达（P=0.04）与总生存期（OS）相关。多因素分析显示，VISTA表达（P=0.01）以及VISTA/CTLA4/PD1的共表达（P=0.05）与较好的OS独立相关，与临床病理特征无关。Kaplan-Meier分析显示，肿瘤细胞（TCs）上VISTA/CTLA4/PDL1和VISTA/CTLA4/PD1检查点的共表达与OS相关（分别为P=0.02和P<0.001）。TCs中的VISTA/CTLA4/PD1和CD4/CD8 TILs与较好的2年OS相关。这种相关性可能是指VISTA作为TCs而非免疫细胞中的受体所起的作用。因此，考虑到VISTA在HGSOC肿瘤细胞中的矛盾作用，靶向阻断VISTA、CTLA4和PD1的联合治疗可能是一种治疗HGSOC的新型且有吸引力的策略。
