γδ T cells are effectors of immunotherapy in cancers with HLA class I defects.
Nature
; 613(7945): 743-750, 2023 01.
Article
em En
| MEDLINE
| ID: mdl-36631610
ABSTRACT
DNA mismatch repair-deficient (MMR-d) cancers present an abundance of neoantigens that is thought to explain their exceptional responsiveness to immune checkpoint blockade (ICB)1,2. Here, in contrast to other cancer types3-5, we observed that 20 out of 21 (95%) MMR-d cancers with genomic inactivation of ß2-microglobulin (encoded by B2M) retained responsiveness to ICB, suggesting the involvement of immune effector cells other than CD8+ T cells in this context. We next identified a strong association between B2M inactivation and increased infiltration by γδ T cells in MMR-d cancers. These γδ T cells mainly comprised the Vδ1 and Vδ3 subsets, and expressed high levels of PD-1, other activation markers, including cytotoxic molecules, and a broad repertoire of killer-cell immunoglobulin-like receptors. In vitro, PD-1+ γδ T cells that were isolated from MMR-d colon cancers exhibited enhanced reactivity to human leukocyte antigen (HLA)-class-I-negative MMR-d colon cancer cell lines and B2M-knockout patient-derived tumour organoids compared with antigen-presentation-proficient cells. By comparing paired tumour samples from patients with MMR-d colon cancer that were obtained before and after dual PD-1 and CTLA-4 blockade, we found that immune checkpoint blockade substantially increased the frequency of γδ T cells in B2M-deficient cancers. Taken together, these data indicate that γδ T cells contribute to the response to immune checkpoint blockade in patients with HLA-class-I-negative MMR-d colon cancers, and underline the potential of γδ T cells in cancer immunotherapy.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Genes MHC Classe I
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Linfócitos T
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Antígenos de Histocompatibilidade Classe I
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Receptores de Antígenos de Linfócitos T gama-delta
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Neoplasias do Colo
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Inibidores de Checkpoint Imunológico
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Imunoterapia
Limite:
Humans
Idioma:
En
Revista:
Nature
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Holanda