Abstract B156: Characterization and role of CCR8+ regulatory T-cells in mouse models of malignant melanoma

A. Edwards, M. Skobe, Anita Rogic, M. Bosenberg
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Abstract

Melanoma cells disseminate through lymphatic vasculature into the regional lymph nodes early in disease progression. We found that a large subset of metastatic melanomas express chemokine receptor CCR8. Its principal ligand, CCL1, is constitutively expressed by lymphatic endothelial cells in the lymph node and is further upregulated by inflammation. The CCL1-CCR8 axis is an important checkpoint for melanoma lymph node metastasis, as an inhibition of CCR8 leads to arrest of melanoma cells in collecting lymphatic vessels and prevents lymph node metastasis. Among immune cells, CCR8 is predominantly expressed by regulatory T-cells (Treg) and by activated Th2 cells, and has been implicated mainly in allergic inflammation. Here we characterized CCR8+ immune cells and examined the role of CCR8 in mouse models of melanoma. Using inducible, genetically engineered (Tyr::CreER;BrafCAPtenloxPCtnnb1loxex3) and syngeneic mouse models of melanoma (B16F10) we characterized CCR8 expression on different immune cell subsets in primary tumors and in sentinel lymph nodes by flow cytometry. In primary tumors, CCR8 was exclusively expressed by CD4+ T-cells, with the highest percentage being FOXP3+CCR8+ Tregs. Increased numbers of CD4+FOXP3+CCR8+ Tregs were found in sentinel lymph nodes with metastases, compared to non-tumor-draining lymph nodes and lymph nodes from tumor-naive mice. This also corresponded with an increase in the total number of FOXP3+ T-regs in sentinel lymph nodes, compared to non-tumor draining lymph nodes. We then evaluated the role of CCR8 on B16F10 tumor growth. Tumor growth was significantly reduced in CCR8-/- mice compared to WT mice when anti-tumor immunity was stimulated with Poly(I:C). However, B16F10 tumor growth did not differ between untreated wild-type (WT) and CCR8 -/- mice. These results suggest that targeting CCR8+ Tregs may increase antitumor immune response. Further studies are required to determine the mechanism by which CCR8+ immune cells facilitate melanoma growth and to explore CCR8 as a therapeutic target in melanoma immunotherapy. Citation Format: Andrew K. Edwards, Mihaela Skobe, Anita Rogic, Marcus Bosenberg. Characterization and role of CCR8+ regulatory T-cells in mouse models of malignant melanoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B156.
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摘要:CCR8+调节性t细胞在小鼠恶性黑色素瘤模型中的表征及作用
在疾病进展的早期,黑色素瘤细胞通过淋巴血管扩散到局部淋巴结。我们发现大部分转移性黑色素瘤表达趋化因子受体CCR8。其主要配体CCL1由淋巴结淋巴内皮细胞组成性表达,并在炎症中进一步上调。CCL1-CCR8轴是黑色素瘤淋巴结转移的重要检查点,抑制CCR8可阻止黑色素瘤细胞聚集淋巴管,阻止淋巴结转移。在免疫细胞中,CCR8主要由调节性t细胞(Treg)和活化的Th2细胞表达,主要与过敏性炎症有关。在这里,我们表征了CCR8+免疫细胞,并检测了CCR8在黑色素瘤小鼠模型中的作用。利用诱导型基因工程(Tyr::CreER;BrafCAPtenloxPCtnnb1loxex3)和同基因黑色素瘤小鼠模型(B16F10),我们通过流式细胞术表征了CCR8在原发肿瘤和前哨淋巴结不同免疫细胞亚群中的表达。在原发肿瘤中,CCR8仅由CD4+ t细胞表达,FOXP3+CCR8+ Tregs的表达比例最高。与非肿瘤引流淋巴结和肿瘤初发小鼠的淋巴结相比,在转移的前哨淋巴结中发现CD4+FOXP3+CCR8+ Tregs的数量增加。这也与前哨淋巴结中FOXP3+ T-regs总数的增加相对应,与非肿瘤引流淋巴结相比。然后我们评估了CCR8在B16F10肿瘤生长中的作用。当Poly(I:C)刺激抗肿瘤免疫时,CCR8-/-小鼠的肿瘤生长明显低于WT小鼠。然而,B16F10肿瘤生长在未治疗的野生型(WT)和CCR8 -/-小鼠之间没有差异。这些结果提示靶向CCR8+ Tregs可能会增加抗肿瘤免疫应答。需要进一步的研究来确定CCR8+免疫细胞促进黑色素瘤生长的机制,并探索CCR8作为黑色素瘤免疫治疗的治疗靶点。引文格式:Andrew K. Edwards, Mihaela Skobe, Anita Rogic, Marcus Bosenberg。CCR8+调节性t细胞在小鼠恶性黑色素瘤模型中的表征及作用[摘要]。第四届CRI-CIMT-EATI-AACR国际癌症免疫治疗会议:将科学转化为生存;2018年9月30日至10月3日;纽约,纽约。费城(PA): AACR;癌症免疫学杂志2019;7(2增刊):摘要nr B156。
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