IL-15/IL-15Rα Heterodimeric Complex as Cancer Immunotherapy in Murine Breast Cancer Models.
IL-15/IL-15Rα Heterodimeric Complex as Cancer Immunotherapy in Murine Breast Cancer Models.
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DOI：
10.3389/fimmu.2020.614667
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发表时间：
2020
影响因子：
7.3
通讯作者：
Heller R
中科院分区：
文献类型：
--
作者：
Guo S;Smeltz RB;Nanajian A;Heller R
白细胞介素15 （IL-15）已在临床试验中被评价为一种潜在的治疗实体瘤的方法，但作为一种单一疗法，全身给药IL-15的有效性尚未实现。IL-15受体α (IL-15Rα)能稳定IL-15并增强其生物活性。本研究的目的是检测IL-15/IL-15Rα复合物（IL-15cx）对CD8+ T细胞的活性，并评估其在小鼠乳腺癌模型中的潜在功效。在小鼠乳腺癌模型（Her2/neu转基因和4T1-luc乳腺癌）中，研究了系统重组蛋白在骨髓源性抑制细胞缺失或瘤内基因电转移（GET）的情况下的抗肿瘤效果。与等摩尔单链IL-15相比，IL-15cx具有更好的体内扩增CD8 T细胞的生物活性。T-bet部分参与CD8 T细胞在体内和体外由于IL-15或IL-15cx的扩增。腹腔注射IL-15cx可适度抑制乳腺癌的生长，这与细胞毒性CD8 T细胞频率的增加及其功能的改善有关。骨髓源性抑制细胞（MDSCs）的消耗对小鼠乳腺癌的生长没有影响。IL-15cx治疗可减少小鼠肿瘤中的MDSCs。然而，它也拮抗抗gr -1消耗抗体的作用。IL-15/IL-15Rα质粒肿瘤内GET可提高4T1乳腺癌模型的长期生存率。局部细胞毒性细胞的早期增加与GET治疗和肿瘤完全消退的动物的长期记忆T细胞的增加有关。全身和局部给药IL-15cx显示出两种不同的治疗反应，中度肿瘤生长抑制或异质性肿瘤消退并改善生存。需要进一步的研究来提高IL-15cx作为乳腺癌免疫疗法的疗效。
Interleukin 15 (IL-15) has been evaluated as a potential treatment for solid tumors in clinical trials, but the effectiveness of systemic IL-15 administration as a monotherapy has not been realized. IL-15 receptor alpha (IL-15Rα) can stabilize IL-15 and enhance its bioactivity. The goal of this study was to examine the activity of IL-15/IL-15Rα complex (IL-15cx) to CD8+ T cells and evaluate its potential efficacy in murine breast cancer models. The antitumor efficacy was studied in mouse mammary carcinoma models (Her2/neu transgenic and 4T1-luc mammary cancers) treated with systemic recombinant protein with/without the depletion of myeloid-derived suppressor cells or intra-tumoral gene electrotransfer (GET). IL-15cx shows superior in vivo bioactivity to expand CD8 T cells in comparison to an equimolar single chain IL-15. T-bet is partially involved in CD8 T cell expansion ex vivo and in vivo due to IL-15 or IL-15cx. Intraperitoneal administration of IL-15cx results in a moderate inhibition of breast cancer growth that is associated with an increase in the frequency of cytotoxic CD8 T cells and the improvement of their function. The depletion of myeloid-derived suppressor cells (MDSCs) has no impact on mouse breast cancer growth. IL-15cx treatment diminishes MDSCs in murine tumors. However, it also antagonizes the effects of anti-Gr-1 depleting antibodies. Intratumoral GET with plasmid IL-15/IL-15Rα leads to a long-term survival benefit in 4T1 mammary carcinoma model. An early increase of local cytotoxic cells correlates with GET treatment and an increase of long-term memory T cells results from animals with complete tumor regression. Systemic and local administration of IL-15cx shows two distinct therapeutic responses, a moderate tumor growth inhibition or heterogeneous tumor regressions with survival improvement. Further studies are warranted to improve the efficacy of IL-15cx as an immunotherapy for breast cancer.
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