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Projeto de investigação
Dissecting regulators of anti-tumor gamma-delta T cells for improved solid cancer immunotherapy
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Publicações
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.
Therapeutic avenues for γδ T cells in cancer
Publication . Costa, Gonçalo Palrão; Mensurado, Sofia; Silva-Santos, Bruno
γδ T cells are regarded as promising effector lymphocytes for next-generation cancer immunotherapies. In spite of being relatively rare in human peripheral blood, γδ T cells are more abundant in epithelial tissues where many tumors develop, and have been shown to actively participate in anticancer immunity as cytotoxic cells or as "type 1" immune orchestrators. A major asset of γδ T cells for tackling advanced cancers is their independence from antigen presentation via the major histocompatibility complex, which clearly sets them apart from conventional αβ T cells. Here we discuss the main therapeutic strategies based on human γδ T cells. These include antibody-based bispecific engagers and adoptive cell therapies, either focused on the Vδ1+ or Vδ2+ γδ T-cell subsets, which can be expanded selectively and differentiated or engineered to maximize their antitumor functions. We review the preclinical data that supports each of the therapeutic strategies under development; and summarize the clinical trials being pursued towards establishing γδ T cell-based treatments for solid and hematological malignancies.
Battle of the γδ T cell subsets in the gut
Publication . Mensurado, Sofia; Silva-Santos, Bruno
In a study in Science, Reis et al. describe a temporal segregation of γδ T cell activities in colorectal cancer (CRC). Initially tumor surveillance is orchestrated by interferon-γ (IFN-γ)-producing and cytotoxic γδ T cell subsets, but once the tumor thrives, it becomes infiltrated by interleukin (IL)-17+ γδ T cell subsets that promote its growth.
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.
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Entidade financiadora
Fundação para a Ciência e a Tecnologia
Programa de financiamento
CEEC IND4ed
Número da atribuição
2021.01953.CEECIND/CP1673/CT0007