瑞士洛桑大学George Coukos团队的最新研究探明了组成性和诱导性趋化因子的协同作用使T细胞在实体肿瘤中的移植和免疫攻击成为可能。相关论文于2019年6月10日发表于《Cancer Cell》杂志上。

该课题组研究了趋化因子对T细胞在实体瘤中积累的调控作用。CCL5和CXCL9的过度表达与实体瘤中CD8⁺ T细胞的浸润相关。T细胞浸润需要肿瘤细胞源性CCL5参与，还需要CXCL9对该作用进行放大，而CXL9是干扰素γ（IFNγ）诱导骨髓细胞分泌的。CCL5和CXCL9的共表达揭示了免疫反应性的肿瘤与生存期延长、检查点阻断反应的关系。CCL5在人类肿瘤中的表达缺失与DNA甲基化导致的表观遗传沉默有一定关系。CCL5表达的降低将会导致肿瘤浸润淋巴细胞（TIL）的逐渐耗竭，而迫使CCL5表达可阻止CXCL9表达和防止TIL丢失，并通过IFNγ抑制小鼠肿瘤生长。

据介绍，肿瘤源性CCL5与骨髓细胞分泌的IFNγ诱导的CXCR3配体的协同作用是调节免疫反应性和免疫反应性肿瘤T细胞浸润的关键。

附：英文原文

Title: Cooperation between Constitutive and Inducible Chemokines Enables T Cell Engraftment and Immune Attack in Solid Tumors

Author: Denarda Dangaj, Marine Bruand, Alizée J. Grimm, Sylvie Rusakiewicz, Mauro Delorenzi, George Coukos

Issue&Volume: Jun 10, 2019 Volume 35Issue 6

Abstract: We investigated the role of chemokines in regulating T cell accumulation in solid tumors. CCL5 and CXCL9 overexpression was associated with CD8 + T cell infiltration in solid tumors. T cell infiltration required tumor cell-derived CCL5 and was amplified by IFN-γ-inducible, myeloid cell-secreted CXCL9. CCL5 and CXCL9 coexpression revealed immunoreactive tumors with prolonged survival and response to checkpoint blockade. Loss of CCL5 expression in human tumors was associated with epigenetic silencing through DNA methylation. Reduction of CCL5 expression caused tumor-infiltrating lymphocyte (TIL) desertification, whereas forced CCL5 expression prevented Cxcl9 expression and TILs loss, and attenuated tumor growth in mice through IFN-γ. The cooperation between tumor-derived CCL5 and IFN-γ-inducible CXCR3 ligands secreted by myeloid cells is key for orchestrating T cell infiltration in immunoreactive and immunoresponsive tumors.

DOI: https://doi.org/10.1016/j.ccell.2019.05.004

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30242-9#articleInformation