Singapore Immunology Network, BMSI, A-STAR, Singapore, Singapore.
Cancer Res. 2011 Nov 15;71(22):6997-7009. doi: 10.1158/0008-5472.CAN-11-1466. Epub 2011 Sep 26.
T-cell infiltration is known to impact tumor growth and is associated with cancer patient survival. However, the molecular cues that favor T-cell infiltration remain largely undefined. Here, using a genetically engineered mouse model of melanoma, we show that CXCR3 ligands and CCL5 synergize to attract effector T cells into cutaneous metastases, and their expression inhibits tumor growth. Treatment of tumor-bearing mice with chemotherapy induced intratumoral expression of these chemokines and favored T-cell infiltration into cutaneous tumors. In patients with melanoma, these chemokines were also upregulated in chemotherapy-sensitive lesions following chemotherapy, and correlated with T-cell infiltration, tumor control, and patient survival. We found that dacarbazine, temozolomide, and cisplatin induced expression of T-cell-attracting chemokines in several human melanoma cell lines in vitro. These data identify the induction of intratumoral expression of chemokines as a novel cell-extrinsic mechanism of action of chemotherapy that results in the recruitment of immune cells with antitumor activity. Therefore, identifying chemotherapeutic drugs able to induce the expression of T-cell-attracting chemokines in cancer cells may represent a novel strategy to improve the efficacy of cancer immunotherapy.
T 细胞浸润已知会影响肿瘤生长，并与癌症患者的生存相关。然而，有利于 T 细胞浸润的分子线索在很大程度上仍未得到明确。在这里，我们使用黑色素瘤的基因工程小鼠模型表明，趋化因子受体 3 的配体和 CCL5 协同作用将效应 T 细胞吸引到皮肤转移灶中，它们的表达抑制肿瘤生长。用化疗治疗荷瘤小鼠会诱导这些趋化因子在肿瘤内表达，并有利于 T 细胞浸润到皮肤肿瘤中。在黑色素瘤患者中，这些趋化因子在化疗后对化疗敏感的病变中也上调，并与 T 细胞浸润、肿瘤控制和患者生存相关。我们发现，达卡巴嗪、替莫唑胺和顺铂在体外诱导几种人黑色素瘤细胞系表达吸引 T 细胞的趋化因子。这些数据表明，诱导肿瘤内表达趋化因子是化疗的一种新的细胞外作用机制，导致具有抗肿瘤活性的免疫细胞的募集。因此，鉴定能够诱导癌细胞表达吸引 T 细胞的趋化因子的化疗药物可能代表一种提高癌症免疫治疗疗效的新策略。
