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

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 ina...

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Published in:	Nature (London) Vol. 613; no. 7945; pp. 743 - 750
Main Authors:	de Vries, Natasja L., van de Haar, Joris, Veninga, Vivien, Chalabi, Myriam, Ijsselsteijn, Marieke E., van der Ploeg, Manon, van den Bulk, Jitske, Ruano, Dina, van den Berg, Jose G., Haanen, John B., Zeverijn, Laurien J., Geurts, Birgit S., de Wit, Gijs F., Battaglia, Thomas W., Gelderblom, Hans, Verheul, Henk M. W., Schumacher, Ton N., Wessels, Lodewyk F. A., Koning, Frits, de Miranda, Noel F. C. C., Voest, Emile E.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 26.01.2023 Nature Publishing Group
Subjects:	13/1 13/2 13/21 13/31 13/51 38/91 45/23 631/250/1619/554/2509 631/250/21 631/250/580 631/67/1059/2325 631/67/1504/1885/1393 82/80 Antigen Presentation Antigens beta 2-Microglobulin - deficiency beta 2-Microglobulin - genetics Biopsy Cancer Cancer immunotherapy CD8 antigen Cell Line, Tumor Colon cancer Colonic Neoplasms - drug therapy Colonic Neoplasms - genetics Colonic Neoplasms - immunology Colonic Neoplasms - therapy Colorectal cancer CTLA-4 protein Cytotoxicity Deactivation DNA Mismatch Repair - genetics DNA repair Effector cells Genes Genes, MHC Class I - genetics Histocompatibility antigen HLA Histocompatibility Antigens Class I - genetics Histocompatibility Antigens Class I - immunology Humanities and Social Sciences Humans Immune checkpoint inhibitors Immune Checkpoint Inhibitors - pharmacology Immune Checkpoint Inhibitors - therapeutic use Immunoglobulin-like receptors Immunoglobulins Immunotherapy Inactivation Leukocytes Lymphocytes Lymphocytes T Mann-Whitney U test Metastases Mismatch repair multidisciplinary Mutation Neoantigens Organoids Patients PD-1 protein Receptors, Antigen, T-Cell, gamma-delta - immunology Receptors, KIR Regression analysis Science Science (multidisciplinary) T cell receptors T-Lymphocytes - immunology Tumor cell lines Tumors β2 Microglobulin
ISSN:	0028-0836, 1476-4687, 1476-4687
Online Access:	Get full text
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Summary:	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. γδ T cells contribute to the response to immune checkpoint blockade treatment in patients with HLA-class-I-negative DNA mismatch repair-deficient colon cancers. .
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-022-05593-1