| Autor: |
Vries, N.L. de, Haar, J. van de, Veninga, V., Chalabi, M., Ijsselsteijn, M.E., Ploeg, M. van der, Bulk, J. van den, Ruano, D., Berg, J.G. van den, Haanen, J.B., Zeverijn, L.J., Geurts, B.S., Wit, G.F. de, Battaglia, T.W., Gelderblom, H., Verheul, H.M.W., Schumacher, T.N., Wessels, L.F.A., Koning, F., Miranda, N.F.C.C. de, Voest, E.E. |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Zdroj: |
Nature, 613, 743-750. NATURE PORTFOLIO |
| Popis: |
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 beta 2-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 gamma delta T cells in MMR-d cancers. These gamma delta T cells mainly comprised the V delta 1 and V delta 3 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(+) gamma delta 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 gamma delta T cells in B2M-deficient cancers. Taken together, these data indicate that gamma delta 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 gamma delta T cells in cancer immunotherapy. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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