Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
Molecular Biotechnology Center "Guido Tarone", University of Turin, Turin, Italy.
Front Immunol. 2024 Aug 8;15:1427424. doi: 10.3389/fimmu.2024.1427424. eCollection 2024.
Pancreatic Ductal Adenocarcinoma (PDA) is one of the most aggressive malignancies with a 5-year survival rate of 13%. Less than 20% of patients have a resectable tumor at diagnosis due to the lack of distinctive symptoms and reliable biomarkers. PDA is resistant to chemotherapy (CT) and understanding how to gain an anti-tumor effector response following stimulation is, therefore, critical for setting up an effective immunotherapy.
Proliferation, and cytokine release and TCRB repertoire of from PDA patient peripheral T lymphocytes, before and after CT, were analyzed in vitro in response to four tumor-associated antigens (TAA), namely ENO1, FUBP1, GAPDH and K2C8. Transcriptional state of PDA patient PBMC was investigated using RNA-Seq before and after CT.
CT increased the number of TAA recognized by T lymphocytes, which positively correlated with patient survival, and high IFN-γ production TAA-induced responses were significantly increased after CT. We found that some ENO1-stimulated T cell clonotypes from CT-treated patients were expanded or de-novo induced, and that some clonotypes were reduced or even disappeared after CT. Patients that showed a higher number of effector responses to TAA (high IFN-γ/IL-10 ratio) after CT expressed increased fatty acid-related transcriptional signature. Conversely, patients that showed a higher number of regulatory responses to TAA (low IFN-γ/IL-10 ratio) after CT significantly expressed an increased IRAK1/IL1R axis-related transcriptional signature.
These data suggest that the expression of fatty acid or IRAK1/IL1Rrelated genes predicts T lymphocyte effector or regulatory responses to TAA in patients that undergo CT. These findings are a springboard to set up precision immunotherapies in PDA based on the TAA vaccination in combination with CT.
胰腺导管腺癌 (PDA) 是最具侵袭性的恶性肿瘤之一，5 年生存率为 13%。由于缺乏明显的症状和可靠的生物标志物，不到 20%的患者在诊断时具有可切除的肿瘤。PDA 对化疗 (CT) 具有抵抗力，因此，了解如何在刺激后获得抗肿瘤效应反应对于建立有效的免疫治疗至关重要。
在体外分析了来自 PDA 患者外周血 T 淋巴细胞在 CT 前后对四种肿瘤相关抗原 (TAA)，即 ENO1、FUBP1、GAPDH 和 K2C8 的增殖、细胞因子释放和 TCRB 库，分析了 PDA 患者 PBMC 在 CT 前后的转录状态。
CT 增加了 T 淋巴细胞识别的 TAA 数量，这与患者的生存呈正相关，并且 CT 后 IFN-γ 产生的 TAA 诱导反应显著增加。我们发现，一些来自 CT 治疗患者的 ENO1 刺激 T 细胞克隆型被扩增或新诱导，而一些克隆型在 CT 后减少甚至消失。在 CT 后对 TAA 表现出更高数量效应器反应（高 IFN-γ/IL-10 比）的患者表达增加的脂肪酸相关转录特征。相反，在 CT 后对 TAA 表现出更高数量调节反应（低 IFN-γ/IL-10 比）的患者显著表达增加的 IRAK1/IL1R 轴相关转录特征。
这些数据表明，脂肪酸或 IRAK1/IL1R 相关基因的表达预测了接受 CT 的患者对 TAA 的 T 淋巴细胞效应或调节反应。这些发现为基于 TAA 疫苗接种联合 CT 建立 PDA 的精准免疫治疗提供了基础。
