Abstract：
Transforming growth factor-beta (TGFβ) can limit the efficacy of cancer treatments, including radiotherapy (RT), by inducing an immunosuppressive tumor environment. The association of TGFβ with impaired T cell infiltration and antitumor immunity is known, but the mechanisms by which TGFβ participates in immune cell exclusion and limits the efficacy of antitumor therapies warrant further investigations.
We used the clinically relevant TGFβ receptor 2 (TGFβR2)-neutralizing antibody MT1 and the small molecule TGFβR1 inhibitor LY3200882 and evaluated their efficacy in combination with RT against murine orthotopic models of head and neck and lung cancer.
We demonstrated that TGFβ pathway inhibition strongly increased the efficacy of RT. TGFβR2 antibody upregulated interferon beta expression in tumor-associated macrophages within the irradiated tumors and favored T cell infiltration at the periphery and within the core of the tumor lesions. We highlighted that both the antitumor efficacy and the increased lymphocyte infiltration observed with the combination of MT1 and RT were dependent on type I interferon signaling.
These data shed new light on the role of TGFβ in limiting the efficacy of RT, identifying a novel mechanism involving the inhibition of macrophage-derived type I interferon production, and fostering the use of TGFβR inhibition in combination with RT in therapeutic strategies for the management of head and neck and lung cancer.
We used the clinically relevant TGFβ receptor 2 (TGFβR2)-neutralizing antibody MT1 and the small molecule TGFβR1 inhibitor LY3200882 and evaluated their efficacy in combination with RT against murine orthotopic models of head and neck and lung cancer.
We demonstrated that TGFβ pathway inhibition strongly increased the efficacy of RT. TGFβR2 antibody upregulated interferon beta expression in tumor-associated macrophages within the irradiated tumors and favored T cell infiltration at the periphery and within the core of the tumor lesions. We highlighted that both the antitumor efficacy and the increased lymphocyte infiltration observed with the combination of MT1 and RT were dependent on type I interferon signaling.
These data shed new light on the role of TGFβ in limiting the efficacy of RT, identifying a novel mechanism involving the inhibition of macrophage-derived type I interferon production, and fostering the use of TGFβR inhibition in combination with RT in therapeutic strategies for the management of head and neck and lung cancer.
摘要：
转化生长因子-β（TGFβ）可以限制癌症治疗的疗效。包括放疗（RT），通过诱导免疫抑制的肿瘤环境。TGFβ与受损的T细胞浸润和抗肿瘤免疫的关联是已知的，但TGFβ参与免疫细胞排斥和限制抗肿瘤治疗疗效的机制需要进一步研究.
我们使用了临床相关的TGFβ受体2（TGFβR2）中和抗体MT1和小分子TGFβR1抑制剂LY3200882，并评估了它们与RT联合对头颈部和肺癌小鼠原位模型的疗效。
我们证明了TGFβ途径抑制强烈增加了RT的功效。TGFβR2抗体上调受照射的肿瘤内肿瘤相关巨噬细胞中的干扰素β表达，并有利于肿瘤病变周围和核心的T细胞浸润。我们强调，MT1和RT联合观察到的抗肿瘤功效和淋巴细胞浸润增加都依赖于I型干扰素信号传导。
这些数据为TGFβ在限制RT疗效中的作用提供了新的思路，鉴定涉及抑制巨噬细胞衍生的I型干扰素产生的新机制，并促进在头颈部和肺癌的治疗策略中结合使用TGFβR抑制剂与RT。
我们使用了临床相关的TGFβ受体2（TGFβR2）中和抗体MT1和小分子TGFβR1抑制剂LY3200882，并评估了它们与RT联合对头颈部和肺癌小鼠原位模型的疗效。
我们证明了TGFβ途径抑制强烈增加了RT的功效。TGFβR2抗体上调受照射的肿瘤内肿瘤相关巨噬细胞中的干扰素β表达，并有利于肿瘤病变周围和核心的T细胞浸润。我们强调，MT1和RT联合观察到的抗肿瘤功效和淋巴细胞浸润增加都依赖于I型干扰素信号传导。
这些数据为TGFβ在限制RT疗效中的作用提供了新的思路，鉴定涉及抑制巨噬细胞衍生的I型干扰素产生的新机制，并促进在头颈部和肺癌的治疗策略中结合使用TGFβR抑制剂与RT。
