CCL5 mediates CD40-driven CD4+ T cell tumor infiltration and immunity
CCL5 mediates CD40-driven CD4+ T cell tumor infiltration and immunity
复制标题
DOI：
10.1172/jci.insight.137263
复制
发表时间：
2020-05-21
期刊：
影响因子：
8
通讯作者：
Vonderheide, Robert H.
中科院分区：
文献类型：
--
作者：
Huffman, Austin P.;Lin, Jeffrey H.;Vonderheide, Robert H.
与CO8(+)T细胞的细胞毒作用相比，人们对CD4(+)T细胞在肿瘤免疫中的作用认识较少。尽管有明确的证据表明在多种免疫疗法中存在对CD4(+)T细胞的依赖，但对CD4(+)T细胞渗入肿瘤的机制仍知之甚少。我们小组先前的研究表明，在胰腺癌小鼠模型中，细胞表面肿瘤坏死因子超家族成员CD40的系统性激活推动T细胞向肿瘤中渗透，并与免疫检查点阻断相结合，导致肿瘤的持久消退和治愈，这依赖于CD8(+)和CD4(+)T细胞。在这里，我们使用单细胞转录本来检测在免疫检查点阻断或不阻断免疫检查点的情况下，激动剂CD40抗体治疗后的肿瘤微环境。我们发现，肿瘤内的髓系细胞在CD40激动剂的作用下产生趋化因子CCLS，并且CCL5介导CD4(+)T细胞进入肿瘤微环境。CCLS基因或药理学上的破坏可以减少CD4(+)T细胞进入肿瘤，但不能减少CD8(+)T细胞的涌入，从而削弱免疫治疗的疗效。这些发现突显了CCL5在有效免疫治疗中选择性地介导CD4(+)T细胞肿瘤侵袭的先前未被认识的作用。
The role CD4(+) T cells play in tumor immunity is less well appreciated than the cytotoxic role of CO8(+) T cells. Despite clear evidence for CD4(+) T cell dependency across multiple immunotherapies, the mechanisms by which CD4(+) T cells infiltrate tumors remain poorly understood. Prior studies by our group have shown in a mouse model of pancreatic cancer that systemic activation of the cell surface TNF superfamily member CD40 drives T cell infiltration into tumors and, in combination with immune checkpoint blockade, leads to durable tumor regressions and cures that depend on both CD8(+) and CD4(+) T cells. Here, we used single-cell transcriptomics to examine the tumor microenvironment following treatment with agonist CD40 antibody with or without immune checkpoint blockade. We show that intratumor myeloid cells produce the chemokine CCLS in response to CD40 agonist and that CCL5 mediates an influx of CD4(+) T cells into the tumor microenvironment. Disruption of CCLS genetically or pharmacologically mitigates the influx of CD4(+) but not CD8(+) T cells into tumors and blunts the therapeutic efficacy of immunotherapy. These findings highlight a previously unappreciated role for CCL5 in selectively mediating CD4(+) T cell tumor infiltration in response to effective immunotherapy.