Disi An, Guoying Chen, Wei-Yi Cheng, Katja Mohrs, Christina Adler, Namita T Gupta, Gurinder S Atwal, David J DiLillo, Christopher Daly, John C Lin, Frank Kuhnert
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引用次数: 0
Abstract
The presence of high endothelial venules (HEV) and tertiary lymphoid structures (TLS) in solid tumors is correlated with favorable prognosis and better responses to immune checkpoint blockade in many cancer types. Elucidation of the molecular mechanisms underlying intratumoral HEV and TLS formation and their contribution to antitumor responses may facilitate the development of improved treatment strategies. Lymphotoxin β receptor (LTβR) signaling is a critical regulator of lymph node organogenesis and can cooperate with antiangiogenic and immune checkpoint blockade treatment to augment tumor-associated HEV formation. In this study, we demonstrated that LTβR signaling modulates the tumor microenvironment via multiple mechanisms to promote antitumor T-cell responses. Systemic activation of the LTβR pathway via agonistic antibody treatment induced tumor-specific HEV formation, upregulated the expression of TLS-related chemokines, and enhanced dendritic cell (DC) and T-cell infiltration and activation in syngeneic tumor models. In vitro studies confirmed direct effects of LTβR agonism on DC activation and maturation and associated DC-mediated T-cell activation. Single-agent LTβR agonist treatment inhibited syngeneic tumor growth in a CD8+ T-cell-dependent and HEV-dependent manner, and the LTβR agonist enhanced antitumor effects of anti-PD-1 and CAR T-cell therapies. An in vivo tumor screen for TLS-inducing cytokines revealed that the combination of LTβR agonism and lymphotoxin ⍺ expression promoted robust intratumoral TLS induction and enhanced tumor responses to anti-CTLA4 treatment. Collectively, this study highlights crucial functions of LTβR signaling in modulating the tumor microenvironment and could inform future HEV/TLS-based strategies for cancer treatments. Significance: LTβR mediates tumor-specific high endothelial venule formation and immunomodulation of the tumor microenvironment that promotes antitumor immune responses, supporting LTβR agonism as an approach to enhance the antitumor efficacy of immunotherapies.
在许多癌症类型中,实体瘤中高内皮静脉(HEV)和三级淋巴结构(TLS)的存在与良好的预后和对免疫检查点阻断(ICB)更好的反应相关。阐明瘤内 HEV 和 TLS 形成的分子机制及其对抗肿瘤反应的贡献可能有助于开发出更好的治疗策略。淋巴毒素β受体(LTβR)信号传导是淋巴结器官形成的关键调节因子,可与抗血管生成和ICB治疗合作,增强肿瘤相关HEV的形成。在这里,我们证明了 LTβR 信号通过多种机制调节肿瘤微环境以促进抗肿瘤 T 细胞反应。通过激动抗体治疗全身激活 LTβR 通路可诱导肿瘤特异性 HEV 的形成,上调 TLS 相关趋化因子的表达,并增强树突状细胞(DC)和 T 细胞在合成肿瘤模型中的浸润和活化。体外研究证实了 LTβR 激动对 DC 活化和成熟以及相关的 DC 介导的 T 细胞活化的直接影响。单剂 LTβR 激动剂治疗能以 CD8+ T 细胞和 HEV 依赖性方式抑制合成肿瘤的生长,LTβR 激动剂还能增强抗 PD-1 和 CAR T 细胞疗法的抗肿瘤效果。对体内肿瘤TLS诱导细胞因子的筛选显示,LTβR激动和淋巴毒素α(LT⍺)表达的结合促进了肿瘤内TLS的强效诱导,增强了肿瘤对抗CTLA-4治疗的反应。总之,这项研究强调了LTβR信号在调节肿瘤微环境中的关键功能,并为未来基于HEV/TLS的癌症治疗策略提供了参考。
期刊介绍:
Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research.
With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445.
Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.