Department of Regenerative Medicine, Kanazawa Medical University, Kahoku 920-0293, Ishikawa, Japan.
Center for Regenerative medicine, Kanazawa Medical University Hospital, Kahoku 920-0293, Ishikawa, Japan.
Int J Mol Sci. 2022 Oct 12;23(20):12177. doi: 10.3390/ijms232012177.
Malignant pleural effusion (MPE) provides a liquid tumor microenvironment model that includes cancer cells and immune cells. However, the characteristics of tumor antigen-specific CD8 T cells have not been investigated in detail. Here, we analyzed MPE samples taken from a patient with pancreatic cancer who received a dendritic cell vaccine targeting Wilms' Tumor 1 (WT1) antigen over the disease course (two points at MPE and 2, two months after MPE1). Epithelial cell adhesion molecule (EpCAM) cancer cells (PD-L1 or T cell immunoglobulin mucin-3, TIM-3), both PD-1 or TIM-3 positive CD8 T cells, and CD14CD68CD163TIM-3 macrophages increased from the MPE to MPE. The ratio of WT1-specific cytotoxic lymphocytes (WT1-CTLs) to MPE CD8 T cells and IFN-γ secretion of WT1-CTLs were reduced with disease progression. Coincidentally, the fraction of central memory T (T) of WT1-CTLs was decreased. On the other hand, CD8 T cells in response to SMAD4, which is homogeneously expressed in EpCAM cancer cells, were detected using in vitro expansion with the HLA-A*11:01 restrictive SVCVNLYH neoantigen. Furthermore, the CD8 T cell response to SMAD4 was diminished following remarkably decreased numbers of CD8 T in MPE samples. In conclusion, CD8 T cells responding to WT1 or SMAD4 neoantigen expressed in EpCAM pancreatic cancer cells were detected in MPE. A tumor antigen-specific immune response would provide novel insight into the MPE microenvironment.
恶性胸腔积液(MPE)提供了一个液体肿瘤微环境模型,其中包括癌细胞和免疫细胞。然而,肿瘤抗原特异性 CD8 T 细胞的特征尚未被详细研究。在这里,我们分析了一位接受针对 Wilms' Tumor 1(WT1)抗原的树突状细胞疫苗治疗的胰腺癌患者的 MPE 样本,该患者在疾病过程中(MPE1 时的两个时间点和 MPE1 后两个月)接受了治疗。上皮细胞黏附分子(EpCAM)癌细胞(PD-L1 或 T 细胞免疫球蛋白粘蛋白-3,TIM-3)、PD-1 或 TIM-3 阳性 CD8 T 细胞和 CD14+CD68+CD163+TIM-3 巨噬细胞从 MPE 增加到 MPE。WT1 特异性细胞毒性淋巴细胞(WT1-CTL)与 MPE CD8 T 细胞的比例和 WT1-CTL 的 IFN-γ分泌随着疾病的进展而降低。巧合的是,WT1-CTL 中央记忆 T(T)的分数减少了。另一方面,使用 HLA-A*11:01 限制性 SVCVNLYH 新抗原,通过体外扩增检测到针对 EpCAM 癌细胞中均匀表达的 SMAD4 的 CD8 T 细胞。此外,在 MPE 样本中 CD8 T 细胞数量明显减少后,对 SMAD4 的 CD8 T 细胞反应减弱。总之,在 EpCAM 胰腺癌细胞中表达的 WT1 或 SMAD4 新抗原的 CD8 T 细胞在 MPE 中被检测到。肿瘤抗原特异性免疫反应将为 MPE 微环境提供新的见解。