Chemoattractant Receptors BLT1 and CXCR3 Regulate Antitumor Immunity by Facilitating CD8+ T Cell Migration into Tumors.
Chemoattractant Receptors BLT1 and CXCR3 Regulate Antitumor Immunity by Facilitating CD8+ T Cell Migration into Tumors.
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DOI：
10.4049/jimmunol.1502376
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发表时间：
2016-09-01
期刊：
影响因子：
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通讯作者：
Haribabu B
中科院分区：
文献类型：
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作者：
Chheda ZS;Sharma RK;Jala VR;Luster AD;Haribabu B
免疫疗法已经显示出相当大的疗效，用于治疗各种癌症，但许多患者仍然没有反应的各种原因，包括不良归巢的T细胞进入肿瘤。在这项研究中，我们研究了白三烯B4受体-BLT 1和CXCR 3的作用，CXCL 9，CXCL 10和CXCL 11的受体在内源性以及疫苗诱导的抗肿瘤免疫反应中的同基因小鼠B16黑色素瘤模型。与WT小鼠相比，在BLT 1 −/−和CXCR 3 −/−小鼠中观察到肿瘤生长显著加速和存活率降低。肿瘤浸润白细胞的分析显示，与WT肿瘤相比，BLT 1-/-和CXCR 3-/-小鼠肿瘤中的CD 8 + T细胞显着减少，尽管它们在外周的频率相似。WT而不是BLT 1 −/−或CXCR 3 −/− CTL的连续转移显著降低了Rag 2 −/−小鼠的肿瘤生长，这一功能归因于敲除（KO）CTL向肿瘤中的浸润减少。共转移实验表明WT CTL不促进KO CTL向肿瘤的浸润。抗PD-1治疗降低了WT小鼠的肿瘤生长速率，但在BLT 1 −/−、CXCR 3 −/−或BLT 1 −/− CXCR 3 −/−小鼠中没有。效力的丧失与在抗PD 1治疗后敲除CTL未能浸润到肿瘤中相关，表明在介导基于抗PD-1的抗肿瘤免疫应答中对BLT 1和CXCR 3两者的专性需求。这些结果证明了BLT 1和CXCR 3在CTL向肿瘤迁移中的关键作用，因此可以靶向增强基于CTL的免疫疗法的功效。
Immunotherapies have shown considerable efficacy for the treatment of various cancers but a multitude of patients remain unresponsive for various reasons including poor homing of T cells into tumors. In this study, we investigated the roles of leukotriene B4 receptor - BLT1; and CXCR3, the receptor for CXCL9, CXCL10 and CXCL11 under endogenous as well as vaccine induced anti-tumor immune response in a syngeneic murine model of B16 melanoma. Significant acceleration in tumor growth and reduced survival was observed in both BLT1−/− and CXCR3−/− mice as compared to the WT mice. Analysis of tumor infiltrating leukocytes revealed significant reduction of CD8+ T-cells in the tumors of BLT1−/− and CXCR3−/− mice as compared to WT tumors, despite their similar frequencies in periphery. Adoptive transfer of WT but not BLT1−/− or CXCR3−/− CTLs significantly reduced tumor growth in Rag2−/− mice, a function attributed to reduced infiltration of knockout (KO) CTLs into tumors. Co-transfer experiments suggested that WT CTLs do not facilitate the infiltration of KO CTLs to tumors. Anti-PD-1 treatment reduced the tumor growth rate in WT mice but not in BLT1−/−, CXCR3−/− or BLT1−/−CXCR3−/− mice. The loss of efficacy correlated with failure of the knockout CTLs to infiltrate into tumors upon anti-PD1 treatment, suggesting an obligate requirement for both BLT1 and CXCR3 in mediating anti-PD-1 based anti-tumor immune response. These results demonstrate a critical role for both BLT1 and CXCR3 in CTL migration to tumors and thus may be targeted to enhance efficacy of CTL based immunotherapies.