γδ T cells are effectors of immunotherapy in cancers with HLA class I defects

γδ T cells are effectors of immunotherapy in cancers with HLA class I defects

de Vries, Natasja L. (Leiden University Medical Center)
van de Haar, Joris (Netherlands Cancer Institute; Oncode Institute)
Veninga, Vivien (Netherlands Cancer Institute; Oncode Institute)
Chalabi, Myriam (Netherlands Cancer Institute)
Ijsselsteijn, Marieke E. (Leiden University Medical Center)
van der Ploeg, Manon (Leiden University Medical Center)
van den Bulk, Jitske (Leiden University Medical Center)
Ruano, Dina (Leiden University Medical Center)
Wessels, L.F.A. (TU Delft Pattern Recognition and Bioinformatics; Netherlands Cancer Institute; Oncode Institute)

2023

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 types^3–5, we observed that 20 out of 21 (95%) MMR-d cancers with genomic inactivation of β2-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.

http://resolver.tudelft.nl/uuid:f1545ac4-8d77-43c5-9173-34d6e5e222fa

https://doi.org/10.1038/s41586-022-05593-1

0028-0836

Nature: international weekly journal of science, 613 (7945), 743-750

Institutional Repository

journal article

© 2023 Natasja L. de Vries, Joris van de Haar, Vivien Veninga, Myriam Chalabi, Marieke E. Ijsselsteijn, Manon van der Ploeg, Jitske van den Bulk, Dina Ruano, L.F.A. Wessels, More Authors