Regulation of gamma-delta T cells in the tumor microenvironment and their manipulation towards immunotherapy of solid cancers

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Dual modulation of cytotoxic and checkpoint receptors tunes the efficacy of adoptive Delta One T cell therapy against colorectal cancer

Publication . Blanco Dominguez, 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

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.

2025Journal article

Open access

γδ T cells maintain sensitivity to immunotherapy in MHC-I-deficient tumors

Publication . Silva-Santos, Bruno; Mensurado, Sofia

Loss of human leukocyte antigen (HLA) class I expression is a major immune evasion mechanism, given the strict requirement of HLA-class-I-mediated antigen presentation for cytotoxic CD8+ T cell activation and tumor cell recognition. In that context, how tumors may remain sensitive to immunotherapy, namely immune checkpoint blockade (ICB), is a highly relevant biological and medical question. A recent study in Nature by de Vries et al. focused on a subgroup of patients with colorectal cancer (CRC) and found that HLA-class-I-deficient tumors retain responsiveness to ICB based on the expansion and effector functions of γδ T cells.

2023Journal article

Restricted access