免疫检查点阻断疗法缓解全身炎症，对非进展型非小细胞肺癌患者中表达细胞FLIP的单核髓源性抑制细胞产生影响。
Immune checkpoint blockade therapy mitigates systemic inflammation and affects cellular FLIP-expressing monocytic myeloid-derived suppressor cells in non-progressor non-small cell lung cancer patients.
发表日期：2023
作者：
Annalisa Adamo, Cristina Frusteri, Sara Pilotto, Simone Caligola, Lorenzo Belluomini, Ornella Poffe, Luca Giacobazzi, Silvia Dusi, Chiara Musiu, Yushu Hu, Tian Wang, Davide Rizzini, Antonio Vella, Stefania Canè, Giulia Sartori, Jessica Insolda, Marco Sposito, Ursula Cesta Incani, Carmine Carbone, Geny Piro, Francesca Pettinella, Fang Qi, Dali Wang, Silvia Sartoris, Francesco De Sanctis, Patrizia Scapini, Stefano Dusi, Marco Antonio Cassatella, Emilio Bria, Michele Milella, Vincenzo Bronte, Stefano Ugel
来源：
CYTOKINE & GROWTH FACTOR REVIEWS
摘要：
癌细胞偏好产生具有免疫抑制和炎症特征的髓系细胞，包括髓源性抑制细胞(MDSCs)，MDSCs有助于肿瘤的进展。抗凋亡分子细胞免疫FLICE抑制蛋白(c-FLIP)是一种重要的caspase-8调节因子，对单核细胞(M)-MDSCs的发展和功能是必需的。在这里，我们评估了免疫检查点抑制剂(ICI)治疗对非小细胞肺癌(NSCLC)患者的系统免疫景观，包括FLIP表达MDSCs的影响。周围免疫参数的纵向变化与患者的预后相关。具体来说，我们招募了34名NSCLC患者，并根据RECIST评估将其分为进展者(P)和非进展者(NP)。我们证明，在ICI治疗后，只有NP患者的促炎细胞因子（如IL-8、IL-6和IL-1β）减少。此外，通过t-分布随机邻居嵌入(t-SNE)和聚类分析，我们发现NP患者的淋巴细胞数量显著增加，而中性粒细胞和单核细胞等髓系细胞略微收缩。尽管ICI对髓系细胞的变化适度，但我们在NP患者的M-MDSCs中同时观察到了c-FLIP表达的明显减少，即使在基线时NP和P患者的表达水平相同。与c-FLIP表达一致，从T0开始，P和NP患者的单核细胞显示出相似的免疫抑制功能；然而，在T1时，仅NP患者群中的这种促肿瘤活性受到了负面影响。因此，ICI治疗可以缓解系统性炎症并影响MDSCs依赖性的免疫抑制。© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.
Cancer cells favor the generation of myeloid cells with immunosuppressive and inflammatory features, including myeloid-derived suppressor cells (MDSCs), which support tumor progression. The anti-apoptotic molecule, cellular FLICE (FADD-like interleukin-1β-converting enzyme)-inhibitory protein (c-FLIP), which acts as an important modulator of caspase-8, is required for the development and function of monocytic (M)-MDSCs. Here, we assessed the effect of immune checkpoint inhibitor (ICI) therapy on systemic immunological landscape, including FLIP-expressing MDSCs, in non-small cell lung cancer (NSCLC) patients. Longitudinal changes in peripheral immunological parameters were correlated with patients' outcome. In detail, 34 NSCLC patients were enrolled and classified as progressors (P) or non-progressors (NP), according to the RECIST evaluation. We demonstrated a reduction in pro-inflammatory cytokines such as IL-8, IL-6, and IL-1β in only NP patients after ICI treatment. Moreover, using t-distributed stochastic neighbor embedding (t-SNE) and cluster analysis, we characterized in NP patients a significant increase in the amount of lymphocytes and a slight contraction of myeloid cells such as neutrophils and monocytes. Despite this moderate ICI-associated alteration in myeloid cells, we identified a distinctive reduction of c-FLIP expression in M-MDSCs from NP patients concurrently with the first clinical evaluation (T1), even though NP and P patients showed the same level of expression at baseline (T0). In agreement with the c-FLIP expression, monocytes isolated from both P and NP patients displayed similar immunosuppressive functions at T0; however, this pro-tumor activity was negatively influenced at T1 in the NP patient cohort exclusively. Hence, ICI therapy can mitigate systemic inflammation and impair MDSC-dependent immunosuppression.© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.