Fan Aaron E, Sultan Hussein, Kumai Takumi, Fesenkova Valentyna I, Wu Juan, Klement John D, Bernstock Joshua D, Friedman Gregory K, Celis Esteban
Division of Pediatrics, Neuro-Oncology Section, MD Anderson Cancer Center, Houston, Texas.
Georgia Cancer Center, Augusta University, Augusta, Georgia.
Mol Cancer Ther. 2025 Mar 4;24(3):419-430. doi: 10.1158/1535-7163.MCT-24-0505.
Adoptive cell therapy (ACT) using retrovirally transduced T cells represents a promising strategy for enhancing antitumor responses. When used with TriVax, a peptide vaccination strategy, this approach synergistically expands antigen-specific cell populations. STAT5 plays a vital role as a transcription factor in regulating T-cell proliferation and their differentiation into effector and memory T cells. We aimed to explore the combination therapy using CD8 T cells engineered to express constitutively active STAT5 (CA-STAT5) with vaccines. CD8 T cells were transduced with a retrovirus (RV) encoding the mouse gp100 T-cell receptor (TCR). In certain treatment groups, cells were also co-transduced with RV encoding CA-STAT5. We assessed transduction efficiency and functional activity through flow cytometry and various functional assays. B16F10 tumor-bearing mice were treated with ACT using RV-transduced CD8 T cells and subsequently vaccinated with TriVax. We demonstrate that TriVax selectively enhanced the expansion of ACT cell populations bearing gp100-specific TCRs. T cells engineered to express CA-STAT5 showed not only increased expansion and polyfunctionality but also reduced PD-1 expression, leading to decreased cellular exhaustion. In a B16F10 melanoma mouse model, our approach yielded a potent antitumor effect, with CA-STAT5 further amplifying this response. We found that CA-STAT5 improved antitumor activities, in part, by attenuating the PD-1/PD-L1 inhibitory pathway. These findings indicate that TCR-transduced CD8 T cells can undergo antigen-dependent expansion when exposed to TriVax. Additionally, the expression of CA-STAT5 enhances T-cell proliferation and persistence, partly by promoting resistance to PD-1/PD-L1-mediated inhibition in antitumor T cells.
使用逆转录病毒转导的T细胞进行过继性细胞疗法（ACT）是增强抗肿瘤反应的一种有前景的策略。当与肽疫苗接种策略TriVax联合使用时，这种方法可协同扩大抗原特异性细胞群体。信号转导及转录激活因子5（STAT5）作为一种转录因子，在调节T细胞增殖及其分化为效应T细胞和记忆T细胞方面起着至关重要的作用。我们旨在探索将经基因工程改造以组成型表达活性STAT5（CA-STAT5）的CD8 T细胞与疫苗联合使用的疗法。用编码小鼠gp100 T细胞受体（TCR）的逆转录病毒（RV）转导CD8 T细胞。在某些治疗组中，细胞还与编码CA-STAT5的RV共转导。我们通过流式细胞术和各种功能测定评估转导效率和功能活性。用RV转导的CD8 T细胞对荷B16F10肿瘤的小鼠进行ACT治疗，随后用TriVax进行疫苗接种。我们证明TriVax选择性增强了携带gp100特异性TCR的ACT细胞群体的扩增。经基因工程改造以表达CA-STAT5的T细胞不仅显示出扩增增加和多功能性增强，而且PD-1表达降低，导致细胞耗竭减少。在B16F10黑色素瘤小鼠模型中，我们的方法产生了强大的抗肿瘤作用，CA-STAT5进一步增强了这种反应。我们发现CA-STAT5部分通过减弱PD-1/PD-L1抑制途径来改善抗肿瘤活性。这些发现表明，经TCR转导的CD8 T细胞在接触TriVax时可经历抗原依赖性扩增。此外，CA-STAT5的表达增强了T细胞的增殖和持久性，部分原因是促进了抗肿瘤T细胞对PD-1/PD-L1介导的抑制的抗性。
