Sorafenib, a multitargeted antiangiogenic tyrosine kinase inhibitor, is the standard of care for patients with advanced hepatocellular carcinoma (HCC). Cumulating evidence suggests that sorafenib differentially affects immune cells; however, whether this immunomodulatory effect has any impact on antitumor immune responses is unknown. Using an orthotopic mouse model of HCC and tumor-free mice, we investigated the effects of sorafenib on antitumor immunity and characterized the underlying mechanisms. Sorafenib treatment inhibited tumor growth and augmented antitumor immune responses in mice bearing established orthotopic HCC. The tumor-specific effector T cell functions were upregulated, while the proportion of PD-1-expressing CD8(+) T cells and regulatory T cells (Tregs) was reduced in tumor microenvironment of sorafenib-treated mice. Mechanistically, the sorafenib-mediated effects on Tregs could be independent of its direct tumor-suppressing activities. Sorafenib treatment reduced Treg numbers by inhibiting their proliferation and inducing apoptosis. Moreover, sorafenib inhibited the function of Tregs, characterized by diminished expression of Treg-associated molecules important for their function and by their impaired suppressive capacity. These data reveal that sorafenib treatment enhanced functions of tumor-specific effector T cells as well as relieved PD-1-mediated intrinsic and Treg-mediated non-cell-autonomous inhibitions in tumor microenvironment leading to effective antitumor immune responses. In addition to the well-known tumor-inhibiting activity of sorafenib, its enhancement of antitumor immunity may also contribute to the clinical efficacy. Our findings uncover a previously unrecognized mechanism of action of sorafenib and indicate that sorafenib represents a potential targeted agent suitable to be combined with immunotherapeutic approaches to treat cancer patients.

中文翻译：

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索拉非尼可减轻肿瘤微环境中效应T细胞的细胞内和细胞外抑制，从而增强抗肿瘤免疫力。

索拉非尼是一种多靶点抗血管生成酪氨酸激酶抑制剂，是晚期肝细胞癌（HCC）患者的治疗标准。越来越多的证据表明索拉非尼可不同地影响免疫细胞。然而，这种免疫调节作用是否对抗肿瘤免疫反应有影响尚不清楚。使用原位肝癌和无肿瘤小鼠模型，我们研究了索拉非尼对抗肿瘤免疫的影响并描述了其潜在机制。索拉非尼治疗可抑制已建立原位肝癌的小鼠的肿瘤生长并增强其抗肿瘤免疫反应。索拉非尼治疗小鼠的肿瘤微环境中，肿瘤特异性效应T细胞功能上调，而表达PD-1的CD8（+）T细胞和调节性T细胞（Tregs）的比例降低。从机理上讲，索拉非尼介导的对Treg的作用可能与其直接的肿瘤抑制活性无关。索拉非尼治疗通过抑制Treg的增殖并诱导其凋亡来降低Treg的数量。此外，索拉非尼抑制Tregs的功能，其特征在于对于其功能重要的Treg相关分子的表达减少以及其抑制能力受损。这些数据表明索拉非尼治疗增强了肿瘤特异性效应T细胞的功能，并减轻了PD-1介导的内源性和Treg介导的肿瘤微环境中非细胞自主性抑制，从而导致了有效的抗肿瘤免疫反应。除了众所周知的索拉非尼具有抑制肿瘤的活性外，其抗肿瘤免疫力的增强也可能有助于临床疗效。