Department of Radiation Oncology, University of California San Francisco, San Francisco, California.
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
Cancer Immunol Res. 2019 Feb;7(2):306-320. doi: 10.1158/2326-6066.CIR-18-0310. Epub 2018 Dec 11.
Transforming growth factor β (TGFβ) is an effector of immune suppression and contributes to a permissive tumor microenvironment that compromises effective immunotherapy. We identified a correlation between and genes expressed by myeloid cells, but not granulocytes, in The Cancer Genome Atlas lung adenocarcinoma data, in which high expression was associated with poor survival. To determine whether TGFβ affected cell fate decisions and lineage commitment, we studied primary cultures of CD14 monocytes isolated from peripheral blood of healthy donors. We discovered that TGFβ was a survival factor for CD14 monocytes, which rapidly executed an apoptotic program in its absence. Continued exposure to TGFβ in combination with granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 6 (IL6) amplified HLA-DRCD14CD11bCD33 myeloid-derived suppressor cells (MDSCs) at the expense of macrophage and dendritic cell (DC) differentiation. MDSCs generated in the presence of TGFβ were more effective in suppressing T-cell proliferation and promoted the T regulatory cell phenotype. In contrast, inhibition of TGFβ signaling using a small-molecule inhibitor of receptor kinase activity in CD14 monocytes treated with GM-CSF and IL6 decreased MDSC differentiation and increased differentiation to proinflammatory macrophages and antigen-presenting DCs. The effect of autocrine and paracrine TGFβ on myeloid cell survival and lineage commitment suggests that pharmacologic inhibition of TGFβ-dependent signaling in cancer would favor antitumor immunity.
转化生长因子 β（TGFβ）是免疫抑制的效应因子，有助于形成有利于肿瘤生长的微环境，从而影响免疫治疗的效果。我们在癌症基因组图谱肺腺癌数据中发现，髓系细胞（而非粒细胞）表达的 和 基因之间存在相关性，其中 高表达与预后不良相关。为了确定 TGFβ 是否影响细胞命运决定和谱系分化，我们研究了从健康供体外周血分离的 CD14 单核细胞的原代培养物。我们发现，TGFβ是 CD14 单核细胞的存活因子，在缺乏 TGFβ 的情况下，单核细胞会迅速执行凋亡程序。持续暴露于 TGFβ 联合粒细胞-巨噬细胞集落刺激因子（GM-CSF）和白细胞介素 6（IL6）会扩增 HLA-DR+CD14+CD11b+CD33+髓系来源抑制细胞（MDSCs），而巨噬细胞和树突状细胞（DC）的分化则受到抑制。在 TGFβ 存在的情况下产生的 MDSCs 能更有效地抑制 T 细胞增殖，并促进 T 调节细胞表型。相比之下，用 GM-CSF 和 IL6 处理的 CD14 单核细胞中，用受体激酶活性的小分子抑制剂抑制 TGFβ 信号通路，会减少 MDSC 分化，增加促炎巨噬细胞和抗原呈递 DC 的分化。TGFβ 对髓系细胞存活和谱系分化的自分泌和旁分泌作用表明，在癌症中抑制 TGFβ 依赖性信号可能有利于抗肿瘤免疫。
