Glucocorticoids do not inhibit antitumor activity of activated CD8+ T cells
Glucocorticoids do not inhibit antitumor activity of activated CD8+ T cells
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DOI：
10.1097/01.cji.0000177999.95831.7b
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发表时间：
2005-11-01
影响因子：
3.9
通讯作者：
Restifio, NP
中科院分区：
文献类型：
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作者：
Hinrichs, CS;Palmer, DC;Restifio, NP
糖皮质激素是一种有效的免疫抑制药物，通常不允许接受免疫治疗的癌症患者服用。我们试图验证糖皮质激素在过继转移后可能干扰细胞功能的假设。我们给B16黑色素瘤荷瘤鼠给予地塞米松，一种有效的合成糖皮质激素，接受PMEL-1 T细胞受体转基因CD8(+)细胞的过继细胞转移(ACT)。地塞米松导致严重的淋巴衰竭，但令人惊讶的是，无论是在ACT之前、期间还是之后，地塞米松并没有改变以ACT为基础的方案的抗肿瘤效果。地塞米松可显著降低受体小鼠的CD8(+)脾细胞数量，但不影响ACT来源的CD8(+)PMEL-1细胞的数量。体外增殖实验显示地塞米松对初治的Pinel-1 CD8(+)细胞有明显的抑制作用，而对活化的细胞无明显影响。体外激活的PMEL-1 CD8(+)细胞释放干扰素-γ可被地塞米松部分抑制，但与对幼稚细胞的几乎完全抑制相比，这种抑制作用相对较小。因此，糖皮质激素对初治的CD8(+)T细胞有明显的抑制作用，但对活化的CD8(+)PMEL-1T细胞的增殖和功能影响不大。最后，在该模型中，由于糖皮质激素对肿瘤消退没有影响，因此在接受基于ACT的免疫治疗方案的一些患者中使用糖皮质激素是可能的。
Glucocorticoids are potent immunosuppressive drugs that are generally withheld from cancer patients receiving immunotherapy. We Sought to test the hypothesis that glucocorticoids might interfere with the function of cells after adoptive transfer. We gave dexamethasone, a potent synthetic glucocorticoid, to B16 melanoma-bearing truce receiving the adoptive cell transfer (ACT) of pmel-1 T-cell receptor transgenic CD8(+) cells. Dexamethasone caused a profound lymphodepletion but, surprisingly, did not alter the anti-tumor efficacy of ACT-based regimens whether given before, during, or after ACT. Although dexamethasone radically decreased the number of native CD8(+) splenocytes in recipient mice, it did not affect the numbers of CD8(+) pmel-1 cells derived from ACT in these mice. In vitro proliferation assays revealed acute inhibition of naive pinel-1 CD8(+) cells by dexamethasone without significant effect on activated cells. In vitro interferon (IFN)-gamma release from activated pmel-1 CD8(+) cells showed partial inhibition by dexamethasone, but this effect was relatively minor when compared with the near-complete inhibition of naive cells. Thus, gucocorticoids had a profound inhibitory effect oil naive CD8(+) T cells but had little impact on the proliferation and function of activated CD8(+) pmel-1 T cells. Finally, because glucocorticoids had no effect on tumor regression in this model, it may be possible to use glucocorticoids in some patients receiving ACT-based immunotherapy regimens.