Targeting CXCL12 from FAP-expressing carcinomaassociated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer
Targeting CXCL12 from FAP-expressing carcinomaassociated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer
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DOI：
10.1073/pnas.1320318110
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发表时间：
2013-12-10
影响因子：
11.1
通讯作者：
Fearon, Douglas T.
中科院分区：
文献类型：
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作者：
Feig, Christine;Jones, James O.;Fearon, Douglas T.
胰腺导管腺癌（PDA）的原位模型允许分析为什么免疫治疗对这种人类疾病无效。尽管发现携带PDA的小鼠具有癌细胞特异性CD8(+) T细胞，但与人类PDA患者一样，这些小鼠对两种促进T细胞功能的免疫检查点拮抗剂没有反应：抗细胞毒性T淋巴细胞相关蛋白4 （α - ctla -4）和α -程序性细胞死亡1配体1 （α - pd - l1）。然而，通过消耗表达成纤维细胞激活蛋白（FAP）的癌α相关成纤维细胞（CAFs），可以实现对PDA生长的免疫控制。FAP（+）基质细胞的耗竭也揭示了α - ctla -4和α - pd - l1的抗肿瘤作用，表明其免疫抑制活性解释了这些t细胞检查点拮抗剂的失败。三个结果表明趋化因子（C-X-C基序）配体12 （CXCL12）解释了FAP（+）细胞的主要免疫抑制：肿瘤中含有癌细胞的区域不存在T细胞，癌细胞被趋化因子CXCL12包裹，FAP+ CAF是肿瘤中CXCL12的主要来源。给药AMD3100，一种CXCL12受体趋化因子（C-X-C基序）受体4抑制剂，诱导癌细胞中t细胞的快速积累，并与α - pd - l1协同作用，大大减少癌细胞，通过其Trp53基因杂合性的丧失而鉴定。残余肿瘤仅由癌前上皮细胞和炎性细胞组成。因此，来自单一基质细胞类型FAP(+) CAF的单一蛋白CXCL12可能在人PDA模型中指导肿瘤免疫逃避。
An autochthonous model of pancreatic ductal adenocarcinoma (PDA) permitted the analysis of why immunotherapy is ineffective in this human disease. Despite finding that PDA-bearing mice had cancer cell-specific CD8(+) T cells, the mice, like human patients with PDA, did not respond to two immunological checkpoint antagonists that promote the function of T cells: anti-cytotoxic T-lymphocyte- associated protein 4 (alpha-CTLA-4) and alpha-programmed cell death 1 ligand 1 (alpha-PD-L1). Immune control of PDA growth was achieved, however, by depleting carcinom alpha-associated fibroblasts (CAFs) that express fibroblast activation protein (FAP). The depletion of the FAP(+) stromal cell also uncovered the antitumor effects of alpha-CTLA-4 and alpha-PD-L1, indicating that its immune suppressive activity accounts for the failure of these T-cell checkpoint antagonists. Three findings suggested that chemokine (C-X-C motif) ligand 12 (CXCL12) explained the overriding immunosuppression by the FAP(+) cell: T cells were absent from regions of the tumor containing cancer cells, cancer cells were coated with the chemokine, CXCL12, and the FAP+ CAF was the principal source of CXCL12 in the tumor. Administering AMD3100, a CXCL12 receptor chemokine (C-X-C motif) receptor 4 inhibitor, induced rapid T-cell accumulation among cancer cells and acted synergistically with alpha-PD-L1 to greatly diminish cancer cells, which were identified by their loss of heterozygosity of Trp53 gene. The residual tumor was composed only of premalignant epithelial cells and inflammatory cells. Thus, a single protein, CXCL12, from a single stromal cell type, the FAP(+) CAF, may direct tumor immune evasion in a model of human PDA.