Histological evaluation of intratumoral myxoma virus treatment in an immunocompetent mouse model of melanoma
Histological evaluation of intratumoral myxoma virus treatment in an immunocompetent mouse model of melanoma
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DOI：
10.2147/ov.s37971
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发表时间：
2013-01-01
影响因子：
6.7
通讯作者：
MacNeill, Amy L.
中科院分区：
文献类型：
--
作者：
Doty, Rosalinda A.;Liu, Jia;MacNeill, Amy L.
在免疫活性小鼠的侵袭性 B16F10 黑色素瘤模型中评估了两种重组粘液瘤病毒（表达荧光蛋白 [MYXV-Tred] 的 MYXV 和编码鼠白细胞介素 15 [MYXV-IL15] 的 MYXV-Tred）的治疗效果。据推测，肿瘤内 IL-15 的持续表达将招募细胞毒性效应细胞来诱导抗肿瘤免疫反应并提高治疗效果。每周进行瘤内注射，以评估治疗对携带已确定的 B16F10 黑色素瘤的 C57BL/6 小鼠的中位生存时间的影响。接受 MYXV-Tred 或 MYXV-IL15 治疗的小鼠的寿命明显长于接受治疗对照的小鼠。出乎意料的是，MYXV-IL15 治疗的小鼠的中位生存时间与 MYXV 治疗的小鼠相似。接种后 1、2 和 4 天，病毒噬斑测定检测到治疗肿瘤内 MYXV-Tred 和 MYXV-IL15 的复制。在 MYXV-IL15 治疗的肿瘤中的这些时间点，与其他治疗组相比，IL-15 浓度、淋巴细胞等级和分化簇 3+ 细胞计数显着增加。然而，接种后 7 天，肿瘤内的病毒滴度、重组蛋白表达和淋巴细胞数量迅速减少。这些数据表明，重组 MYXV 治疗应至少每 4 天重复一次，以维持鼠肿瘤内重组蛋白的表达。此外，在早期时间点，经 MYXV-Tred 和 MYXV-IL15 治疗的肿瘤中，中性粒细胞炎症显着增加。据推测，重组 MXYV 的瘤内复制诱导的中性粒细胞炎症有助于 MYXV 治疗在此黑色素瘤模型中的抗肿瘤作用。这些发现支持将中性粒细胞趋化因子纳入重组痘病毒溶瘤病毒疗法中。
Two recombinant myxoma viruses (MYXV expressing a fluorescent protein [MYXV-Tred] and MYXV-Tred encoding murine interleukin-15 [MYXV-IL15]) were evaluated for therapeutic effects in an aggressive B16F10 melanoma model in immunocompetent mice. It was hypothesized that continuous expression of IL-15 within a tumor would recruit cytotoxic effector cells to induce an antitumor immune response and improve treatment efficacy. Weekly intratumoral injections were given to evaluate the effect of treatment on the median survival time of C57BL/6 mice bearing established B16F10 melanomas. Mice that received MYXV-Tred or MYXV-IL15 lived significantly longer than mice given treatment controls. Unexpectedly, the median survival time of MYXV-IL15-treated mice was similar to that of MYXV-treated mice. At 1, 2, and 4 days postinoculation, viral plaque assays detected replicating MYXV-Tred and MYXV-IL15 within treated tumors. At these time points in MYXV-IL15-treated tumors, IL-15 concentration, lymphocyte grades, and cluster of differentiation-3+ cell counts were significantly increased when compared to other treatment groups. However, viral titers, recombinant protein expression, and lymphocyte numbers within the tumors diminished rapidly at 7 days postinoculation. These data indicate that treatment with recombinant MYXV should be repeated at least every 4 days to maintain recombinant protein expression within a murine tumor. Additionally, neutrophilic inflammation was significantly increased in MYXV-Tred-and MYXV-IL15-treated tumors at early time points. It is speculated that neutrophilic inflammation induced by intratumoral replication of recombinant MXYV contributes to the antitumoral effect of MYXV treatment in this melanoma model. These findings support the inclusion of neutrophil chemotaxins in recombinant poxvirus oncolytic virotherapy.