Surgery/Oncology & Microbiology/Immunology, Emory University, Atlanta, Georgia, USA
School of Medicine, Emory University, Atlanta, Georgia, USA.
J Immunother Cancer. 2024 Jun 30;12(6):e008715. doi: 10.1136/jitc-2023-008715.
How distinct methods of host preconditioning impact the efficacy of adoptively transferred antitumor T helper cells is unknown.
CD4 T cells with a transgenic T-cell receptor that recognize tyrosinase-related peptide (TRP)-1 melanoma antigen were polarized to the T helper 17 (Th17) phenotype and then transferred into melanoma-bearing mice preconditioned with either total body irradiation or chemotherapy.
We found that preconditioning mice with a non-myeloablative dose of total body irradiation (TBI of 5 Gy) was more effective than using an equivalently dosed non-myeloablative chemotherapy (cyclophosphamide (CTX) of 200 mg/kg) at augmenting therapeutic activity of antitumor TRP-1 Th17 cells. Antitumor Th17 cells engrafted better following preconditioning with TBI and regressed large established melanoma in all animals. Conversely, only half of mice survived long-term when preconditioned with CTX and infused with anti-melanoma Th17 cells. Interleukin (IL)-17 and interferon-γ, produced by the infused Th17 cells, were detected in animals given either TBI or CTX preconditioning. Interestingly, inflammatory cytokines (granulocyte colony stimulating factor, IL-6, monocyte chemoattractant protein-1, IL-5, and keratinocyte chemoattractant) were significantly elevated in the serum of mice preconditioned with TBI versus CTX after Th17 therapy. The addition of fludarabine (FLU, 200 mg/kg) to CTX (200 mg/kg) improved the antitumor response to the same degree mediated by TBI, whereas FLU alone with Th17 therapy was ineffective.
Our results indicate, for the first time, that the antitumor response, persistence, and cytokine profiles resulting from Th17 therapy are impacted by the specific regimen of host preconditioning. This work is important for understanding mechanisms that promote long-lived responses by adoptive cellular therapy, particularly as CD4 based T-cell therapies are now emerging in the clinic.
采用不同的宿主预处理方法对过继转移的抗肿瘤辅助性 T 细胞疗效的影响尚不清楚。
将具有识别酪氨酸酶相关肽（TRP）-1 黑色素瘤抗原的转基因 T 细胞受体的 CD4 T 细胞极化到辅助性 T 细胞 17（Th17）表型，然后转移到接受全身照射或化疗预处理的黑色素瘤荷瘤小鼠体内。
我们发现，用非致死剂量的全身照射（5Gy 的 TBI）预处理小鼠比用等效剂量的非致死性非骨髓清除化疗（200mg/kg 的环磷酰胺（CTX））更有效地增强抗肿瘤 TRP-1 Th17 细胞的治疗活性。TBI 预处理后，抗肿瘤 Th17 细胞植入更好，所有动物的大黑色素瘤均消退。相反，CTX 预处理并输注抗黑色素瘤 Th17 细胞的小鼠只有一半能长期存活。用 TBI 或 CTX 预处理的动物均检测到输注的 Th17 细胞产生的白细胞介素（IL）-17 和干扰素-γ。有趣的是，Th17 治疗后，TBI 预处理的小鼠血清中炎症细胞因子（粒细胞集落刺激因子、IL-6、单核细胞趋化蛋白-1、IL-5 和角质形成细胞趋化因子）显著升高，而 CTX 预处理后，FLU（200mg/kg）联合 CTX（200mg/kg）可改善 TBI 介导的抗肿瘤反应，而单独使用 FLU 联合 Th17 治疗则无效。
我们的研究结果首次表明，Th17 治疗的抗肿瘤反应、持久性和细胞因子谱受宿主预处理方案的影响。这项工作对于理解通过过继细胞疗法促进长期反应的机制非常重要，特别是因为基于 CD4 的 T 细胞疗法现在正在临床上出现。
