Department of Immunology and Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
Department of Laboratory Animal Science, Fudan University, Shanghai, 200032, China.
Proc Natl Acad Sci U S A. 2021 Apr 20;118(16). doi: 10.1073/pnas.2024171118.
Macrophages are the key regulator of T-cell responses depending on their activation state. C-C motif chemokine receptor-like 2 (CCRL2), a nonsignaling atypical receptor originally cloned from LPS-activated macrophages, has recently been shown to regulate immune responses under several inflammatory conditions. However, whether CCRL2 influences macrophage function and regulates tumor immunity remains unknown. Here, we found that tumoral CCRL2 expression is a predictive indicator of robust antitumor T-cell responses in human cancers. CCRL2 is selectively expressed in tumor-associated macrophages (TAM) with immunostimulatory phenotype in humans and mice. Conditioned media from tumor cells could induce CCRL2 expression in macrophages primarily via TLR4, which is negated by immunosuppressive factors. mice exhibit accelerated melanoma growth and impaired antitumor immunity characterized by significant reductions in immunostimulatory macrophages and T-cell responses in tumor. Depletion of CD8 T cells or macrophages eliminates the difference in tumor growth between WT and mice. Moreover, CCRL2 deficiency impairs immunogenic activation of macrophages, resulting in attenuated antitumor T-cell responses and aggravated tumor growth in a coinjection tumor model. Mechanically, CCRL2 interacts with TLR4 on the cell surface to retain membrane TLR4 expression and further enhance its downstream Myd88-NF-κB inflammatory signaling in macrophages. Similarly, mice exhibit reduced CCRL2 expression in TAM and accelerated melanoma growth. Collectively, our study reveals a functional role of CCRL2 in activating immunostimulatory macrophages, thereby potentiating antitumor T-cell response and tumor rejection, and suggests CCLR2 as a potential biomarker candidate and therapeutic target for cancer immunotherapy.
巨噬细胞是调节 T 细胞反应的关键调节因子，取决于其激活状态。C-C 基序趋化因子受体样 2（CCRL2）是一种非信号转导的非典型受体，最初从 LPS 激活的巨噬细胞中克隆，最近已被证明在几种炎症条件下调节免疫反应。然而，CCRL2 是否影响巨噬细胞功能并调节肿瘤免疫仍然未知。在这里，我们发现肿瘤中的 CCRL2 表达是人类癌症中强大抗肿瘤 T 细胞反应的预测指标。CCRL2 在人类和小鼠中选择性表达于具有免疫刺激性表型的肿瘤相关巨噬细胞（TAM）中。肿瘤细胞的条件培养基可主要通过 TLR4 诱导巨噬细胞中 CCRL2 的表达，而免疫抑制因子可否定这一作用。TLR4 缺陷型 小鼠表现出黑色素瘤生长加速和抗肿瘤免疫受损的特征，表现为免疫刺激性巨噬细胞和肿瘤中的 T 细胞反应显著减少。耗尽 CD8 T 细胞或巨噬细胞消除了 WT 和 小鼠之间在肿瘤生长方面的差异。此外，CCRL2 缺陷会损害巨噬细胞的免疫原性激活，导致抗肿瘤 T 细胞反应减弱，并在共注射肿瘤模型中加剧肿瘤生长。在机制上，CCRL2 与细胞表面上的 TLR4 相互作用，以保留膜 TLR4 的表达，并进一步增强其下游 Myd88-NF-κB 炎症信号转导。同样，TLR4 缺陷型 小鼠中的 TAM 中 CCRL2 表达减少，黑色素瘤生长加速。总之，我们的研究揭示了 CCRL2 在激活免疫刺激性巨噬细胞中的功能作用，从而增强抗肿瘤 T 细胞反应和肿瘤排斥反应，并表明 CCRL2 作为癌症免疫治疗的潜在生物标志物候选物和治疗靶标。
