小柯机器人

近日，英国帝国理工学院George Kassiotis等研究人员合作发现，针对内源性逆转录病毒的抗体可促进肺癌免疫治疗。相关论文于2023年4月12日在线发表于国际学术期刊《自然》。

据研究人员介绍，B细胞经常出现在实体瘤的边缘，作为异位淋巴器官的有组织滤泡，这被称为三级淋巴结构（TLS）。尽管TLS已被发现与病人生存率的提高和对免疫检查点阻断（ICB）的反应有关，但这种关联的基本机制仍然难以捉摸。

研究人员报道了TRACERx 421（通过治疗追踪非小细胞肺癌演变）和其他肺癌队列的患者以及最近建立的肺腺癌免疫原性小鼠模型中的肺驻留B细胞反应。研究人员发现人类和小鼠肺腺癌都能引起局部生发中心反应和肿瘤结合抗体，并进一步确定内源性逆转录病毒（ERV）包膜糖蛋白是一个主要的抗肿瘤抗体靶标。ERV靶向B细胞反应在人类和小鼠中都被ICB放大，在小鼠模型中被KRAS（G12C）的靶向抑制放大。ERV反应性抗体发挥了抗肿瘤活性，延长了小鼠模型的生存期，ERV的表达预测了人类肺腺癌的ICB结果。

最后，研究人员发现小鼠模型中有效的免疫疗法需要CXCL13依赖性的TLS形成。相反，治疗性CXCL13治疗能增强抗肿瘤免疫力，并与ICB协同作用。这些发现为TLS与免疫治疗反应的关联提供了一个可能的机制基础。

附：英文原文

Title: Antibodies against endogenous retroviruses promote lung cancer immunotherapy

Author: Ng, Kevin W., Boumelha, Jesse, Enfield, Katey S. S., Almagro, Jorge, Cha, Hongui, Pich, Oriol, Karasaki, Takahiro, Moore, David A., Salgado, Roberto, Sivakumar, Monica, Young, George, Molina-Arcas, Miriam, de Carn Trcesson, Sophie, Anastasiou, Panayiotis, Fendler, Annika, Au, Lewis, Shepherd, Scott T. C., Martnez-Ruiz, Carlos, Puttick, Clare, Black, James R. M., Watkins, Thomas B. K., Kim, Hyemin, Shim, Seohee, Faulkner, Nikhil, Attig, Jan, Veeriah, Selvaraju, Magno, Neil, Ward, Sophia, Frankell, Alexander M., Al Bakir, Maise, Lim, Emilia L., Hill, Mark S., Wilson, Gareth A., Cook, Daniel E., Birkbak, Nicolai J., Behrens, Axel, Yousaf, Nadia, Popat, Sanjay, Hackshaw, Allan, Hiley, Crispin T., Litchfield, Kevin, McGranahan, Nicholas, Jamal-Hanjani, Mariam, Larkin, James, Lee, Se-Hoon, Turajlic, Samra, Swanton, Charles, Downward, Julian, Kassiotis, George

Issue&Volume: 2023-04-12

Abstract: B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)1,2. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive1,2. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma3. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.

DOI: 10.1038/s41586-023-05771-9

Source: https://www.nature.com/articles/s41586-023-05771-9

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