肿瘤细胞治疗研究
英文原题：Dual modulation of cytotoxic and checkpoint receptors tunes the efficacy of adoptive Delta One T cell therapy against colorectal cancer.
这些发现支持基于DOT细胞的联合疗法用于CRC治疗。
结直肠癌（CRC）仍然是当前免疫治疗面临的挑战。Vδ1+ γδ T 细胞因其不依赖 HLA-I 的细胞毒作用和天然组织趋向性而提供了一种有前景的替代方案。我们开发了 Delta One T（DOT）细胞，这是一种基于 Vδ1+ γδ T 细胞的过继性细胞疗法，已在血液系统恶性肿瘤中进行了临床探索，但尚未用于实体瘤。在此，我们证明 DOT 细胞能够在体外靶向 CRC 细胞系以及患者来源的标本和类器官，并在 CRC 原位异种移植模型中控制肿瘤生长。尽管如此，我们发现肿瘤浸润性 DOT 细胞表现出细胞毒性和抑制性受体平衡失调，这种失调与内源性 Vδ1+ TIL（肿瘤浸润淋巴细胞）相似，并限制了其细胞毒性。为了最大化疗效，我们揭示了两种策略：通过丁酸盐给药上调 NKG2D 配体来增强靶向，以及阻断检查点 TIGIT 和 PD1，二者协同释放了 DOT 细胞的细胞毒性。这些发现支持基于 DOT 细胞的联合方案用于 CRC 治疗。
Colorectal cancer (CRC) remains a challenge for current immunotherapies. Vδ1 + γδ T cells offer a promising alternative because of their HLA-I-independent cytotoxicity and natural tissue tropism. We developed Delta One T (DOT) cells, a Vδ1 + γδ T cell-based adoptive cell therapy clinically explored for hematological malignancies but not yet for solid tumors. Here we demonstrate the capacity of DOT cells to target CRC cell lines and patient-derived specimens and organoids in vitro and to control tumor growth in an orthotopic xenograft model of CRC. Notwithstanding, we found tumor-infiltrating DOT cells to exhibit a dysregulated balance of cytotoxic and inhibitory receptors that paralleled that of endogenous Vδ1 + tumor-infiltrating lymphocytes and limited their cytotoxicity. To maximize efficacy, we unveil two strategies, increasing targeting through upregulation of NKG2D ligands upon butyrate administration and blocking the checkpoints TIGIT and PD1, which synergistically unleashed DOT cell cytotoxicity. These findings support DOT cell-based combinatorial approaches for CRC treatment.
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