Differences of tumor-recruiting myeloid cells in murine squamous cell carcinoma influence the efficacy of immunotherapy combined with a TLR7 agonist and PD-L1 blockade.
Differences of tumor-recruiting myeloid cells in murine squamous cell carcinoma influence the efficacy of immunotherapy combined with a TLR7 agonist and PD-L1 blockade.
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DOI：
10.1016/j.oraloncology.2019.02.014
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发表时间：
2019-04
期刊：
影响因子：
4.8
通讯作者：
H. Tachinami;Naoto Nishii;Yulong Xia;Yoshihisa Kashima;T. Ohno;S. Nagai;Lixin Li;W. Lau;K. Tomihara;M. Noguchi;M. Azuma
中科院分区：
文献类型：
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作者：
H. Tachinami;Naoto Nishii;Yulong Xia;Yoshihisa Kashima;T. Ohno;S. Nagai;Lixin Li;W. Lau;K. Tomihara;M. Noguchi;M. Azuma
目的肿瘤微环境的免疫状态对临床预后有显著影响。在这里，我们研究了免疫环境中的肿瘤浸润性白细胞（TILes）在两个小鼠模型的鳞状细胞癌和比较的免疫抑制剂的影响，包括TLR 7激动剂和免疫检查点抑制剂，和化疗药物，吉西他滨，在这些models.Materials和methodsTILes从NR-S1和SCCVII移植小鼠进行了流式细胞术分析。NR-S1接种的小鼠接受瑞喹莫特（合成TLR 7激动剂）、抗PD-L1抗体或两者，并检查肿瘤生长和TIL。吉西他滨管理耗尽CD 11b +cells. Results50%以上的TILes从NR-S1-和SCCVII接种小鼠的CD 11b +Gr-1+细胞。NR-S1 CD 11b+细胞的主要部分是Ly 6 GlowLy 6Clow-negative F4/80−肿瘤相关中性粒细胞（TAN），而大多数SCCVII CD 11b+细胞是Ly 6 GlowLy 6C −F4/80+肿瘤相关巨噬细胞。NR-S1 TAN不表达MHC II类和CD 86，但表达活性氧和PD-L1。瑞喹莫特单独使用和与抗PD-L1抗体联合使用不会使NR-S1肿瘤消退，但联合使用增加了CD 8 +TILes中的CD 8/调节性T细胞比率以及IFN-γ和PD-1表达。联合治疗前低剂量吉西他滨的预管理抑制NR-S1 tumors.ConclusionsNR-S1肿瘤的进展与丰富的招聘TANs耐治疗与TLR 7激动剂，单独和PD-1阻断相结合，并需要一个额外的吉西他滨治疗。肿瘤浸润性CD 11b+骨髓细胞的表型和状态可能影响免疫抑制剂的疗效。
ObjectivesThe immune status of the tumor microenvironment has a marked impact on clinical outcomes. Here we examined the immune environments of tumor-infiltrating leukocytes (TILes) in two murine models of squamous cell carcinoma and compared the effects of immunotherapeutic agents, including a TLR7 agonist and an immune checkpoint inhibitor, and a chemotherapeutic agent, gemcitabine, in these models.Materials and methodsTILes from NR-S1- and SCCVII-grafted mice were analyzed by flow cytometry. NR-S1-inoculated mice received resiquimod (a synthetic TLR7 agonist), an anti-PD-L1 antibody, or both, and tumor growth and TILs were examined. Gemcitabine was administered to deplete CD11b+cells.ResultsMore than 50% of TILes from NR-S1- and SCCVII-inoculated mice were CD11b+Gr-1+cells. A major fraction of NR-S1 CD11b+cells was Ly6GhighLy6Clow-negaF4/80−tumor-associated neutrophils (TANs) and the majority of SCCVII CD11b+cells were Ly6GlowLy6C−F4/80+tumor-associated macrophages. NR-S1 TANs did not express MHC class II and CD86, but did express reactive oxygen species and PD-L1. Resiquimod, alone and in combination with an anti-PD-L1 antibody, did not regress NR-S1 tumors, but the combination increased the CD8/regulatory T cell-ratio, and IFN-γ and PD-1 expression in CD8+TILes. Pre-administration of low-dose gemcitabine prior to the combination treatment suppressed the progression of NR-S1 tumors.ConclusionsNR-S1 tumors with abundant recruitment of TANs were resistant to treatments with a TLR7 agonist, alone and in combination with PD-1 blockade, and required an additional gemcitabine treatment. The phenotype and status of tumor-infiltrating CD11b+myeloid cells may influence the efficacy of immunotherapeutic agents.