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Abstract：
Chimeric antigen receptor (CAR) T cell therapy is associated with high risk of adverse events. Glucocorticoids (GCs) are cornerstone in the management of high-grade cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Given the potentially deleterious effects of GCs on CAR T cells anti-tumor activity, increasing our understanding of GCs impact on CAR T cells is crucial.
Using several CAR T cells i.e., CD19, mesothelin (MSLN)-CD28 and MSLN-41BB CAR T cells (M28z and MBBz), we compared phenotypical, functional, changes and anti-tumor activity between i) transduced CD19 CAR T cells with untransduced T cells, ii) M28z with MBBz CAR T cells induced by Dexamethasone (Dx) or Methylprednisolone (MP) exposures.
Higher levels of GC receptor were found in less differentiated CAR T cells. Overall, Dx and MP showed a similar impact on CAR T cells. Compared to untreated condition, GCs exposure increased the expression of PD-1 and TIM-3 and reduced the expression of LAG3 and function of T cells and CAR T cells. GC exposures induced more exhausted (LAG3 + PD1 + TIM3 +) and dysfunctional (CD107a-INFγ-TNF-IL2-) untransduced T cells in comparison to CD19 CAR T cells. GC exposure impaired more CD4 + than CD8 + CD19 CAR T cells. GC exposures increased more PD-1 expression associated with reduced proliferative capacity and function of M28z as compared to MBBz CAR T cells. CAR T cells anti-tumor activity was greatly affected by repeated GC exposure but partly recovered within 48h after GCs withdrawal.
In summary, GCs impacted phenotype and function of untransduced and CAR T cell with different magnitude. The nature of the CAR costimulatory domain influenced the magnitude of CAR T cell response to GCs.
Using several CAR T cells i.e., CD19, mesothelin (MSLN)-CD28 and MSLN-41BB CAR T cells (M28z and MBBz), we compared phenotypical, functional, changes and anti-tumor activity between i) transduced CD19 CAR T cells with untransduced T cells, ii) M28z with MBBz CAR T cells induced by Dexamethasone (Dx) or Methylprednisolone (MP) exposures.
Higher levels of GC receptor were found in less differentiated CAR T cells. Overall, Dx and MP showed a similar impact on CAR T cells. Compared to untreated condition, GCs exposure increased the expression of PD-1 and TIM-3 and reduced the expression of LAG3 and function of T cells and CAR T cells. GC exposures induced more exhausted (LAG3 + PD1 + TIM3 +) and dysfunctional (CD107a-INFγ-TNF-IL2-) untransduced T cells in comparison to CD19 CAR T cells. GC exposure impaired more CD4 + than CD8 + CD19 CAR T cells. GC exposures increased more PD-1 expression associated with reduced proliferative capacity and function of M28z as compared to MBBz CAR T cells. CAR T cells anti-tumor activity was greatly affected by repeated GC exposure but partly recovered within 48h after GCs withdrawal.
In summary, GCs impacted phenotype and function of untransduced and CAR T cell with different magnitude. The nature of the CAR costimulatory domain influenced the magnitude of CAR T cell response to GCs.
摘要：
背景：嵌合抗原受体（CAR）T细胞治疗与不良事件的高风险相关。糖皮质激素（GC）是治疗高级细胞因子释放综合征（CRS）和免疫效应细胞相关神经毒性综合征（ICANS）的基石。鉴于GC对CAR-T细胞抗肿瘤活性的潜在有害作用，增加我们对GC对CAR-T细胞的影响的理解是至关重要的。
方法：使用几种CART细胞，即CD19，间皮素（MSLN）-CD28和MSLN-41BBCART细胞（M28z和MBBz），我们比较了表型，功能，i)转导的CD19CART细胞与未转导的T细胞之间的变化和抗肿瘤活性，ii)M28z与由地塞米松(Dx)或甲基强的松龙(MP)暴露诱导的MBBzCART细胞。
结果：在低分化的CAR-T细胞中发现了更高水平的GC受体。总的来说,Dx和MP对CART细胞显示出相似的影响。与未经处理的条件相比，GCs暴露会增加PD-1和TIM-3的表达，并降低LAG3的表达以及T细胞和CART细胞的功能。与CD19CART细胞相比,GC暴露诱导更多的耗尽(LAG3+PD1+TIM3+)和功能失调(CD107a-INFγ-TNF-IL2-)未转导的T细胞。与CD8+CD19CART细胞相比，GC暴露对CD4+的损害更多。与MBBzCART细胞相比，GC暴露增加了与M28z增殖能力和功能降低相关的更多PD-1表达。CART细胞抗肿瘤活性受到反复GC暴露的极大影响，但在GCs撤药后48小时内部分恢复。
结论：总之，GC以不同程度影响未转导和CART细胞的表型和功能。CAR共刺激结构域的性质影响了CART细胞对GC的反应程度。
方法：使用几种CART细胞，即CD19，间皮素（MSLN）-CD28和MSLN-41BBCART细胞（M28z和MBBz），我们比较了表型，功能，i)转导的CD19CART细胞与未转导的T细胞之间的变化和抗肿瘤活性，ii)M28z与由地塞米松(Dx)或甲基强的松龙(MP)暴露诱导的MBBzCART细胞。
结果：在低分化的CAR-T细胞中发现了更高水平的GC受体。总的来说,Dx和MP对CART细胞显示出相似的影响。与未经处理的条件相比，GCs暴露会增加PD-1和TIM-3的表达，并降低LAG3的表达以及T细胞和CART细胞的功能。与CD19CART细胞相比,GC暴露诱导更多的耗尽(LAG3+PD1+TIM3+)和功能失调(CD107a-INFγ-TNF-IL2-)未转导的T细胞。与CD8+CD19CART细胞相比，GC暴露对CD4+的损害更多。与MBBzCART细胞相比，GC暴露增加了与M28z增殖能力和功能降低相关的更多PD-1表达。CART细胞抗肿瘤活性受到反复GC暴露的极大影响，但在GCs撤药后48小时内部分恢复。
结论：总之，GC以不同程度影响未转导和CART细胞的表型和功能。CAR共刺激结构域的性质影响了CART细胞对GC的反应程度。
