Blanco-Domínguez Rafael, Barros Leandro, Carreira Mariana, van der Ploeg Manon, Condeço Carolina, Marsères Gabriel, Ferreira Cristina, Costa Carla, Ferreira Carlos M, Déchanet-Merville Julie, de Miranda Noel F C C, Mensurado Sofia, Silva-Santos Bruno
Gulbenkian Institute for Molecular Medicine, Lisbon, Portugal.
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Nat Cancer. 2025 Apr 16. doi: 10.1038/s43018-025-00948-9.
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.
结直肠癌（CRC）仍然是当前免疫疗法面临的一个挑战。Vδ1 γδ T细胞因其不依赖HLA-I的细胞毒性和天然的组织嗜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，已在临床上对血液系统恶性肿瘤进行探索，但尚未用于实体瘤。在这里，我们证明了DOT细胞在体外靶向CRC细胞系、患者来源的标本和类器官的能力，以及在CRC原位异种移植模型中控制肿瘤生长的能力。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的失调平衡，这与内源性Vδ1肿瘤浸润淋巴细胞的情况相似，并限制了它们的细胞毒性。为了使疗效最大化，我们揭示了两种策略，即通过给予丁酸盐上调NKG2D配体来增强靶向作用，以及阻断检查点TIGIT和PD1，这两种策略协同释放了DOT细胞的细胞毒性。这些发现支持基于DOT细胞的联合方法用于CRC治疗。
