Governa Valeria, Brittoli Alvaro, Mele Valentina, Pinamonti Maurizio, Terracciano Luigi, Muenst Simone, Iezzi Giandomenica, Spagnoli Giulio Cesare, Zajac Paul, Trella Emanuele
Department of Biomedicine, Basel University Hospital and University of Basel, Basel, Switzerland.
Department of Pharmaceutical Sciences, University of Piemonte Orientale, Novara, Italy.
Oncoimmunology. 2019 Feb 14;8(5):e1568162. doi: 10.1080/2162402X.2019.1568162. eCollection 2019.
CD40 triggering may result in antitumor effects of potentially high clinical relevance. To gain insights important for patient selection and to identify adequate targeting techniques, we investigated CD40 expression in human cancer tissues and generated a replication-incompetent recombinant vaccinia virus expressing CD40 ligand (rVV40L). Its effects were explored and upon direct CD40 targeting on malignant cells or macrophage activation. CD40 expression was analyzed by immunohistochemistry in tumor and stromal cells in a multi-tumor array including 836 specimens from 27 different tumor types. Established tumor cell lines were used to explore the capacity of rVV40L to induce malignant cell apoptosis and modulate functional profiles of polarized macrophages. CD40 expression was detectable in significantly higher numbers of stromal as compared to malignant cells in lung and breast cancers. CD40 ligation following rVV40L infection induced apoptosis in CD40(+) cancer cells, but only in the presence of intact specific signal transduction chain. Importantly, rVV40L infection promoted the induction of TNF-α-dependent antitumor activity of M1-like macrophages directed against CD40(-) targets. CD40-activated M1-like macrophages also displayed enhanced ability to CXCL10-dependently recruit CD8+ T cells and to efficiently present cancer cell intracellular antigens through cross-priming. Moreover, rVV-driven CD40L expression partially "re-educated" M2-like macrophages, as suggested by detectable CXCL10 and IL-12 production. Most importantly, we observed that intra-tumoral injection of rVV40L-infected human macrophages inhibits progression of human CD40(-) tumors . First evidences of anticancer activity of rVV40L strongly encourage further evaluations.
CD40激活可能会产生具有潜在高临床相关性的抗肿瘤作用。为了获得对患者选择重要的见解并确定合适的靶向技术，我们研究了人类癌组织中CD40的表达，并构建了一种表达CD40配体的无复制能力的重组痘苗病毒（rVV40L）。我们探讨了其对恶性细胞直接靶向CD40或巨噬细胞激活的作用。通过免疫组织化学分析了一个多肿瘤阵列中肿瘤和基质细胞中的CD40表达，该阵列包括来自27种不同肿瘤类型的836个标本。使用已建立的肿瘤细胞系来探索rVV40L诱导恶性细胞凋亡和调节极化巨噬细胞功能谱的能力。与肺癌和乳腺癌中的恶性细胞相比，在基质细胞中可检测到的CD40表达明显更多。rVV40L感染后CD40连接可诱导CD40(+)癌细胞凋亡，但仅在完整的特定信号转导链存在时才会发生。重要的是，rVV40L感染促进了针对CD40(-)靶标的M1样巨噬细胞的TNF-α依赖性抗肿瘤活性的诱导。CD激活的M1样巨噬细胞还表现出增强的能力，即通过CXCL10依赖性募集CD8+T细胞，并通过交叉提呈有效地呈递癌细胞内抗原。此外，如可检测到的CXCL10和IL-12产生所表明的，rVV驱动的CD40L表达部分地“重新教育”了M2样巨噬细胞。最重要的是，我们观察到瘤内注射rVV40L感染的人类巨噬细胞可抑制人类CD40(-)肿瘤的进展。rVV40L抗癌活性的初步证据强烈鼓励进一步评估。
