Tasquinimod modulates suppressive myeloid cells and enhances cancer immunotherapies in murine models.
Tasquinimod modulates suppressive myeloid cells and enhances cancer immunotherapies in murine models.
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DOI：
10.1158/2326-6066.cir-14-0036
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发表时间：
2015-02
影响因子：
10.1
通讯作者：
Pili R
中科院分区：
文献类型：
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作者：
Shen L;Sundstedt A;Ciesielski M;Miles KM;Celander M;Adelaiye R;Orillion A;Ciamporcero E;Ramakrishnan S;Ellis L;Fenstermaker R;Abrams SI;Eriksson H;Leanderson T;Olsson A;Pili R
肿瘤免疫治疗的一个主要障碍是癌症患者体内存在抑制细胞群，如髓系来源的抑制细胞和肿瘤相关巨噬细胞()，它们有助于促进肿瘤生长和转移的免疫抑制微环境。他奎尼莫特是一种新型的抗肿瘤药物，目前正处于临床开发的后期阶段，用于治疗去势抵抗的前列腺癌。他喹莫特的一个靶点是炎症蛋白S100A9，已被证明影响肿瘤抑制髓系细胞的聚集和功能。在这里，我们报告了他喹莫特对两种不同免疫疗法在小鼠癌症模型中的抗肿瘤作用的显著增强：前列腺癌的肿瘤疫苗(SurVaxM)和黑色素瘤的肿瘤靶向超抗原(TTS)。在组合策略中，他喹莫特抑制不同的M2极化表型(CD206+)的MDSC群体和TAM。从治疗组小鼠肿瘤中分离出的CD11b+髓系细胞表达较低水平的精氨酸酶-1和较高水平的诱导型一氧化氮合酶(INOS)，并且体外免疫抑制作用较弱，当这些细胞与肿瘤细胞共同注射时，其体内促瘤能力显著降低。肿瘤特异性CD8+T细胞在循环和肿瘤中显著增加。此外，T细胞效应功能，包括细胞介导的细胞毒作用和干扰素γ的产生，也得到了增强。综上所述，这些数据表明，他喹莫特对抑制髓系细胞的药理学靶向可产生治疗益处，并为他喹莫特与癌症免疫疗法的临床测试提供了理论基础。
A major barrier for cancer immunotherapy is the presence of suppressive cell populations in cancer patients, such as myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), which contribute to the immunosuppressive microenvironment that promotes tumor growth and metastasis. Tasquinimod is a novel antitumor agent that is currently at an advanced stage of clinical development for treatment of castration-resistant prostate cancer. A target of tasquinimod is the inflammatory protein S100A9, which has been demonstrated to affect the accumulation and function of tumor-suppressive myeloid cells. Here, we report that tasquinimod provided a significant enhancement to the antitumor effects of two different immunotherapeutics in mouse models of cancer: a tumor vaccine (SurVaxM) for prostate cancer and a tumor-targeted superantigen (TTS) for melanoma. In the combination strategies, tasquinimod inhibited distinct MDSC populations and TAMs of the M2-polarized phenotype (CD206+). CD11b+ myeloid cells isolated from tumors of treated mice expressed lower levels of arginase-1 and higher levels of inducible nitric oxide synthase (iNOS), and were less immunosuppressive ex vivo, which translated into a significantly reduced tumor-promoting capacity in vivo when these cells were co-injected with tumor cells. Tumor-specific CD8+ T cells were increased markedly in the circulation and in tumors. Furthermore, T-cell effector functions, including cell-mediated cytotoxicity and IFNγ production, were potentiated. Taken together, these data suggest that pharmacologic targeting of suppressive myeloid cells by tasquinimod induces therapeutic benefit and provide the rationale for clinical testing of tasquinimod in combination with cancer immunotherapies.