Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada.
McMaster Immunology Research Center, McMaster University, Hamilton, ON, Canada.
Front Immunol. 2023 Apr 17;14:1179827. doi: 10.3389/fimmu.2023.1179827. eCollection 2023.
The genesis of SMAC mimetic drugs is founded on the observation that many cancers amplify IAP proteins to facilitate their survival, and therefore removal of these pathways would re-sensitize the cells towards apoptosis. It has become increasingly clear that SMAC mimetics also interface with the immune system in a modulatory manner. Suppression of IAP function by SMAC mimetics activates the non-canonical NF-κB pathway which can augment T cell function, opening the possibility of using SMAC mimetics to enhance immunotherapeutics.
We have investigated the SMAC mimetic LCL161, which promotes degradation of cIAP-1 and cIAP-2, as an agent for delivering transient costimulation to engineered BMCA-specific human TAC T cells. In doing so we also sought to understand the cellular and molecular effects of LCL161 on T cell biology.
LCL161 activated the non-canonical NF-κB pathway and enhanced antigen-driven TAC T cell proliferation and survival. Transcriptional profiling from TAC T cells treated with LCL161 revealed differential expression of costimulatory and apoptosis-related proteins, namely CD30 and FAIM3. We hypothesized that regulation of these genes by LCL161 may influence the drug's effects on T cells. We reversed the differential expression through genetic engineering and observed impaired costimulation by LCL161, particularly when CD30 was deleted. While LCL161 can provide a costimulatory signal to TAC T cells following exposure to isolated antigen, we did not observe a similar pattern when TAC T cells were stimulated with myeloma cells expressing the target antigen. We questioned whether FasL expression by myeloma cells may antagonize the costimulatory effects of LCL161. Fas-KO TAC T cells displayed superior expansion following antigen stimulation in the presence of LCL161, suggesting a role for Fas-related T cell death in limiting the magnitude of the T cell response to antigen in the presence of LCL161.
Our results demonstrate that LCL161 provides costimulation to TAC T cells exposed to antigen alone, however LCL161 did not enhance TAC T cell anti-tumor function when challenged with myeloma cells and may be limited due to sensitization of T cells towards Fas-mediated apoptosis.
SMAC 模拟药物的产生源于这样一个观察结果，即许多癌症会扩增 IAP 蛋白以促进其存活，因此去除这些途径将使细胞重新对细胞凋亡敏感。越来越明显的是，SMAC 模拟物还以调节方式与免疫系统相互作用。SMAC 模拟物抑制 IAP 功能会激活非经典 NF-κB 途径，从而增强 T 细胞功能，这为使用 SMAC 模拟物增强免疫疗法开辟了可能性。
我们研究了 SMAC 模拟物 LCL161，它可促进 cIAP-1 和 cIAP-2 的降解，作为向工程化的 BMCA 特异性人 TAC T 细胞传递短暂共刺激的药物。在这样做的过程中，我们还试图了解 LCL161 对 T 细胞生物学的细胞和分子影响。
LCL161 激活了非经典 NF-κB 途径，并增强了抗原驱动的 TAC T 细胞增殖和存活。用 LCL161 处理的 TAC T 细胞的转录谱分析显示，共刺激和凋亡相关蛋白（即 CD30 和 FAIM3）的差异表达。我们假设 LCL161 对这些基因的调节可能会影响药物对 T 细胞的作用。我们通过基因工程逆转了差异表达，并观察到 LCL161 的共刺激作用受损，尤其是当 CD30 被删除时。虽然 LCL161 在暴露于分离的抗原后可以向 TAC T 细胞提供共刺激信号，但当 TAC T 细胞受到表达靶抗原的骨髓瘤细胞刺激时，我们没有观察到类似的模式。我们质疑骨髓瘤细胞表达的 FasL 是否会拮抗 LCL161 的共刺激作用。在 LCL161 存在的情况下，Fas-KO TAC T 细胞在抗原刺激后表现出更好的扩增，这表明 Fas 相关的 T 细胞死亡在限制 LCL161 存在下 T 细胞对抗原的反应幅度方面起作用。
我们的结果表明，LCL161 向单独暴露于抗原的 TAC T 细胞提供共刺激，但当 TAC T 细胞受到骨髓瘤细胞的挑战时，LCL161 并未增强 TAC T 细胞的抗肿瘤功能，并且可能由于 T 细胞对 Fas 介导的凋亡的敏感性而受到限制。
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