Tumor vaccines expressing flt3 ligand synergize with ctla-4 blockade to reject preimplanted tumors.
Tumor vaccines expressing flt3 ligand synergize with ctla-4 blockade to reject preimplanted tumors.
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DOI：
10.1158/0008-5472.can-08-3289
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发表时间：
2009-10-01
期刊：
影响因子：
11.2
通讯作者：
Allison JP
中科院分区：
文献类型：
--
作者：
Curran MA;Allison JP
健康细胞向恶性肿瘤的转变涉及许多基因突变和基因表达畸变。由于这些变化很少在个体或癌症类型之间共享，因此引发广谱肿瘤免疫的最佳来源仍然是每个患者自己的肿瘤。此前，我们已经证明，结合阻断 T 细胞阴性共刺激分子 CTLA-4 和接种表达 GM-CSF (Gvax) 的受辐射 B16 肿瘤可促进已形成的小鼠黑色素瘤的排斥。在这里，我们表明，与 GM-CSF 一样，在 B16 中表达的细胞因子 Flt3-配体 (Flt3L) 与 CTLA-4 阻断相结合可促进 B16 的预防性和治疗性排斥。当在肿瘤生长部位施用时，Gvax 无法阻止任何小鼠的肿瘤生长，而 B16-Flt3L 疫苗 (Fl3vax) 会诱导接种前 3 天植入的 75% 黑色素瘤发生排斥反应。相对于 Gvax，Fl3vax 促进 CD8+ T 细胞、“前哨”细胞和浆细胞样树突细胞对疫苗部位和肿瘤部位的更大浸润。即使在 CD25+ Treg 耗竭的情况下，Gvax 和 Fl3vax 联合用于治疗 B16 黑色素瘤时也不会产生协同作用。此外，我们还表明，Flt3L 表达和 CTLA-4 阻断的组合也可以促进已建立的 TRAMP 前列腺腺癌的排斥，证明这种治疗的效用不仅限于黑色素瘤。将 Flt3 配体改造为组成型分泌并附加 IgG2a 尾部，产生了 B16 疫苗，当与 CTLA-4 阻断相结合时，与 Gvax 相比，该疫苗可防止明显更多的 5 天植入 B16-BL6 肿瘤的生长。
The transformation of a healthy cell into a malignant neoplasm involves numerous genetic mutations and aberrations in gene expression. As few of these changes are shared between individuals or types of cancer, the best source for eliciting broad-spectrum tumor immunity remains each patient’s own tumor. Previously, we have demonstrated that combining blockade of the T-cell negative costimulatory molecule CTLA-4 and vaccination with irradiated B16 tumor expressing GM-CSF (Gvax) promotes rejection of established murine melanomas. Here we show that, like GM-CSF, the cytokine Flt3-ligand (Flt3L) expressed in B16 and coupled with CTLA-4 blockade promotes both prophylactic and therapeutic rejection of B16. When administered at the site of growing tumor Gvax fails to prevent tumor outgrowth in any mice, whereas the B16-Flt3L vaccine (Fl3vax) induces the rejection of 75% of melanomas implanted 3 days prior to vaccination. Relative to Gvax, Fl3vax promotes greater infiltration of both the vaccine site and the tumor site by CD8+ T-cells and “sentinel” and plasmacytoid dendritic cells. Gvax and Fl3vax did not synergize when used in combination in treating B16 melanoma even in the context of CD25+ Treg depletion. Further, we show that a combination of Flt3L expression and CTLA-4 blockade can also promote the rejection of established TRAMP prostate adenocarcinomas, proving the utility of this treatment extends beyond melanoma. Engineering Flt3-ligand to be constitutively secreted and attaching an IgG2a tail yielded a B16 vaccine which, when combined with CTLA-4 blockade, prevented the outgrowth of significantly more 5-day implanted B16-BL6 tumors than did Gvax.