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%。由于缺乏独特的症状和可靠的生物标志物，不到 20% 的患者在诊断时肿瘤可切除。 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疗法至关重要。PDA 患者外周 T 淋巴细胞的增殖、细胞因子释放和 TCRB 库，之前CT 后，在体外分析对四种肿瘤相关抗原 (TAA) 的反应，即 ENO1、FUBP1、GAPDH 和 K2C8。使用RNA-Seq研究CT前后PDA患者PBMC的转录状态。CT增加了T淋巴细胞识别的TAA数量，这与患者生存呈正相关，并且CT后高IFN-γ产生TAA诱导的反应显着增加。我们发现接受CT治疗的患者中一些ENO1刺激的T细胞克隆型被扩增或从头诱导，而一些克隆型在CT后减少甚至消失。 CT 后对 TAA 表现出更多效应反应（高 IFN-γ/IL-10 比率）的患者表达了增加的脂肪酸相关转录特征。相反，CT 后对 TAA 显示更多调节反应（低 IFN-γ/IL-10 比率）的患者显着表达增加的 IRAK1/IL1R 轴相关转录特征。这些数据表明脂肪酸或 IRAK1 的表达/IL1R 相关基因可预测接受 CT 治疗的患者中 T 淋巴细胞效应或对 TAA 的调节反应。这些发现是基于 TAA 疫苗接种与 CT 相结合的 PDA 精准免疫疗法的跳板。版权所有 © 2024 Brugiapaglia, Bulfamante, Curcio, Arigoni, Calogero, Bonello, Genuardi, Spadi, Satolli, Campra, Giordano, Cappello, Cordero和诺维利。

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.Copyright © 2024 Brugiapaglia, Bulfamante, Curcio, Arigoni, Calogero, Bonello, Genuardi, Spadi, Satolli, Campra, Giordano, Cappello, Cordero and Novelli.