CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Deletion of the protein tyrosine phosphatase PTPN22 for adoptive T cell therapy facilitates CTL effector function but promotes T cell exhaustion.
Deletion of the protein tyrosine phosphatase PTPN22 for adoptive T cell therapy facilitates CTL effector function but promotes T cell exhaustion.
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本研究质疑 TIM-3 是否作为 IR 发挥作用，并强调为了在 ACT 中实现更长期的保护，对 T 细胞进行基因操作需要在短期增强效应功能与 T 细胞耗竭风险之间取得平衡。
过继性细胞治疗（ACT）是一种有前景的癌症治疗策略，但它面临着若干挑战，例如肿瘤微环境中慢性 TCR 刺激诱导的 T 细胞耗竭导致缺乏长期保护。然而，ACT 的一个优势在于它允许进行细胞操作，例如敲除蛋白酪氨酸磷酸酶非受体型 22（PTPN22），从而改善 ACT 中 CD8+ T 细胞的抗肿瘤疗效。我们测试了在有利于 T 细胞耗竭的情境下，Ptpn22 KO 细胞毒性 T 细胞（CTL）是否也比 Ptpn22 WT CTL 更有效地控制肿瘤。
在将少量CTL过继转移至皮下植入MC38肿瘤的小鼠后，评估了Ptpn22 WT和Ptpn22 KO CTL的肿瘤控制能力。分离TIL（肿瘤浸润淋巴细胞）以分析效应功能。建立了一种体外试验，以比较CTL在抗原脉冲肿瘤细胞急性和慢性再刺激下的反应功能。使用ID8肿瘤模型，在体外和体内随时间追踪Ptpn22 WT和Ptpn22 KO T细胞效应蛋白和耗竭相关蛋白的表达。最后，使用单克隆抗体和CRISPR/Cas9介导的敲除，评估了PD-1和TIM-3阻断对Ptpn22 KO CTL肿瘤控制的影响。
尽管在转移时具有改善的效应功能，Ptpn22 KO CTL比Ptpn22 WT CTL更加耗竭，其特征是效应功能更快丧失，以及抑制性受体（IRs）更早和更高表达，尤其是终末耗竭标志物TIM-3。TIM-3表达受转录因子NFIL3控制，由IL-2信号诱导，而IL-2信号在Ptpn22 KO细胞中增强。Ptpn22 KO CTL的抗肿瘤反应在体内PD-1阻断后得到改善，但敲除或抗体介导的TIM-3阻断并未改善反而进一步损害了肿瘤控制，表明TIM-3信号本身并未驱动Ptpn22 KO CTL中所见的 diminished function。
Adoptive cell therapy (ACT) is a promising strategy for treating cancer, yet it faces several challenges such as lack of long-term protection due to T cell exhaustion induced by chronic TCR stimulation in the tumor microenvironment. One benefit of ACT, however, is that it allows for cellular manipulations, such as deletion of the phosphotyrosine phosphatase non-receptor type 22 (PTPN22), which improves CD8 + T cell antitumor efficacy in ACT. We tested whether Ptpn22 KO cytolytic T cells (CTLs) were also more effective than Ptpn22 WT CTL in controlling tumors in scenarios that favor T cell exhaustion.
Tumor control by Ptpn22 WT and Ptpn22 KO CTL was assessed following adoptive transfer of low numbers of CTL to mice with subcutaneously implanted MC38 tumors. Tumor infiltrating lymphocytes were isolated for analysis of effector functions. An in vitro assay was established to compare CTL function in response to acute and chronic restimulation with antigen-pulsed tumor cells. The expression of effector and exhaustion-associated proteins by Ptpn22 WT and Ptpn22 KO T cells was followed over time in vitro and in vivo using the ID8 tumor model. Finally, the effect of PD-1 and TIM-3 blockade on Ptpn22 KO CTL tumor control was assessed using monoclonal antibodies and CRISPR/Cas9-mediated knockout.
Despite having improved effector function at the time of transfer, Ptpn22 KO CTL became more exhausted than Ptpn22 WT CTL, characterized by more rapid loss of effector functions, and earlier and higher expression of inhibitory receptors (IRs), particularly the terminal exhaustion marker TIM-3. TIM-3 expression, under the control of the transcription factor NFIL3, was induced by IL-2 signaling which was enhanced in Ptpn22 KO cells. Antitumor responses of Ptpn22 KO CTL were improved following PD-1 blockade in vivo, yet knockout or antibody-mediated blockade of TIM-3 did not improve but further impaired tumor control, indicating TIM-3 signaling itself did not drive the diminished function seen in Ptpn22 KO CTL.
This study questions whether TIM-3 plays a role as an IR and highlights that genetic manipulation of T cells for ACT needs to balance short-term augmented effector function against the risk of T cell exhaustion in order to achieve longer-term protection.
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