Pellom Samuel T, Dudimah Duafalia F, Thounaojam Menaka C, Uzhachenko Roman V, Singhal Ashutosh, Richmond Ann, Shanker Anil
Department of Biochemistry and Cancer Biology, School of Medicine, Meharry Medical College, Nashville, Tennessee, USA.
Department of Microbiology and Immunology, School of Medicine, Meharry Medical College, Nashville, Tennessee, USA.
Oncotarget. 2017 Jan 31;8(5):8604-8621. doi: 10.18632/oncotarget.14365.
Tumor-induced immune tolerance poses a major challenge for therapeutic interventions aimed to manage cancer. We explored approaches to overcome T-cell suppression in murine breast and kidney adenocarcinomas, and lung fibrosarcoma expressing immunogenic antigens. We observed that treatment with a reversible proteasome inhibitor bortezomib (1 mg/kg body weight) in tumor-bearing mice significantly enhanced the expression of lymphocyte-stimulatory cytokines IL-2, IL-12, and IL-15. Notably, bortezomib administration reduced pulmonary nodules of mammary adenocarcinoma 4T1.2 expressing hemagglutinin (HA) model antigen (4T1HA) in mice. Neutralization of IL-12 and IL-15 cytokines with a regimen of blocking antibodies pre- and post-adoptive transfer of low-avidity HA518-526-specific CD8+T-cells following intravenous injection of 4T1HA cells increased the number of pulmonary tumor nodules. This neutralization effect was counteracted by the tumor metastasis-suppressing action of bortezomib treatments. In bortezomib-treated 4T1HA tumor-bearing mice, CD4+T-cells showed increased IL-2 production, CD11c+ dendritic cells showed increased IL-12 and IL-15 production, and HA-specific activated CD8+T-cells showed enhanced expression of IFNγ, granzyme-B and transcription factor eomesodermin. We also noted a trend of increased expression of IL-2, IL-12 and IL-15 receptors as well as increased phosphorylation of STAT5 in tumor-infiltrating CD8+T-cells following bortezomib treatment. Furthermore, bortezomib-treated CD8+T-cells showed increased phosphorylation of mitogen-activated protein kinase p38, and Akt, which was abrogated by phosphatidylinositide 3-kinase (PI3K) inhibitor. These data support the therapeutic potential of bortezomib in conjunction with other immunotherapies to augment the strength of convergent signals from CD8+T-cell signaling molecules including TCR, cytokine receptors and downstream PI3K/Akt/STAT5 pathways to sustain CD8+T-cell effector function in the tumor microenvironment.
肿瘤诱导的免疫耐受对旨在治疗癌症的干预措施构成了重大挑战。我们探索了克服小鼠乳腺癌、肾腺癌以及表达免疫原性抗原的肺纤维肉瘤中T细胞抑制的方法。我们观察到，给荷瘤小鼠注射可逆性蛋白酶体抑制剂硼替佐米（1毫克/千克体重）可显著增强淋巴细胞刺激细胞因子IL-2、IL-12和IL-15的表达。值得注意的是，硼替佐米给药可减少小鼠体内表达血凝素（HA）模型抗原（4T1HA）的乳腺腺癌4T1.2的肺结节。在用低亲和力HA518-526特异性CD8+T细胞静脉注射4T1HA细胞后，在过继转移前后用阻断抗体方案中和IL-12和IL-15细胞因子，会增加肺肿瘤结节的数量。硼替佐米治疗的肿瘤转移抑制作用抵消了这种中和作用。在硼替佐米治疗的荷4T1HA肿瘤小鼠中，CD4+T细胞的IL-2产生增加，CD11c+树突状细胞的IL-12和IL-15产生增加，HA特异性活化的CD8+T细胞的IFNγ、颗粒酶B和转录因子胚中胚层决定蛋白的表达增强。我们还注意到，硼替佐米治疗后，肿瘤浸润性CD8+T细胞中IL-2、IL-12和IL-15受体的表达有增加趋势，STAT5的磷酸化也增加。此外，硼替佐米处理的CD8+T细胞显示丝裂原活化蛋白激酶p38和Akt的磷酸化增加，而磷脂酰肌醇3激酶（PI3K）抑制剂可消除这种增加。这些数据支持硼替佐米与其他免疫疗法联合使用的治疗潜力，以增强来自CD8+T细胞信号分子（包括TCR、细胞因子受体和下游PI3K/Akt/STAT5途径）的汇聚信号强度，从而维持肿瘤微环境中CD8+T细胞的效应器功能。
