PMID- 36631610
OWN - NLM
STAT- MEDLINE
DCOM- 20230201
LR  - 20230531
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 613
IP  - 7945
DP  - 2023 Jan
TI  - gammadelta T cells are effectors of immunotherapy in cancers with HLA class I defects.
PG  - 743-750
LID - 10.1038/s41586-022-05593-1 [doi]
AB  - 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 
      beta2-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 gammadelta T cells in MMR-d cancers. These gammadelta T cells mainly comprised 
      the Vdelta1 and Vdelta3 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(+) gammadelta 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 gammadelta T cells in 
      B2M-deficient cancers. Taken together, these data indicate that gammadelta 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 gammadelta T 
      cells in cancer immunotherapy.
CI  - (c) 2023. The Author(s).
FAU - de Vries, Natasja L
AU  - de Vries NL
AUID- ORCID: 0000-0003-4966-7036
AD  - Department of Pathology, Leiden University Medical Center, Leiden, The 
      Netherlands.
AD  - Department of Immunology, Leiden University Medical Center, Leiden, The 
      Netherlands.
FAU - van de Haar, Joris
AU  - van de Haar J
AD  - Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, 
      Amsterdam, The Netherlands.
AD  - Oncode Institute, Utrecht, The Netherlands.
AD  - Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, 
      The Netherlands.
FAU - Veninga, Vivien
AU  - Veninga V
AUID- ORCID: 0000-0002-5166-5075
AD  - Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, 
      Amsterdam, The Netherlands.
AD  - Oncode Institute, Utrecht, The Netherlands.
FAU - Chalabi, Myriam
AU  - Chalabi M
AUID- ORCID: 0000-0002-8607-6174
AD  - Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, 
      Amsterdam, The Netherlands.
AD  - Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, The 
      Netherlands.
AD  - Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
FAU - Ijsselsteijn, Marieke E
AU  - Ijsselsteijn ME
AD  - Department of Pathology, Leiden University Medical Center, Leiden, The 
      Netherlands.
FAU - van der Ploeg, Manon
AU  - van der Ploeg M
AUID- ORCID: 0000-0001-7150-3068
AD  - Department of Pathology, Leiden University Medical Center, Leiden, The 
      Netherlands.
FAU - van den Bulk, Jitske
AU  - van den Bulk J
AUID- ORCID: 0000-0002-2056-9478
AD  - Department of Pathology, Leiden University Medical Center, Leiden, The 
      Netherlands.
FAU - Ruano, Dina
AU  - Ruano D
AD  - Department of Pathology, Leiden University Medical Center, Leiden, The 
      Netherlands.
FAU - van den Berg, Jose G
AU  - van den Berg JG
AD  - Department of Pathology, Netherlands Cancer Institute, Amsterdam, The 
      Netherlands.
FAU - Haanen, John B
AU  - Haanen JB
AUID- ORCID: 0000-0001-5884-7704
AD  - Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, 
      Amsterdam, The Netherlands.
AD  - Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
FAU - Zeverijn, Laurien J
AU  - Zeverijn LJ
AD  - Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, 
      Amsterdam, The Netherlands.
AD  - Oncode Institute, Utrecht, The Netherlands.
FAU - Geurts, Birgit S
AU  - Geurts BS
AD  - Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, 
      Amsterdam, The Netherlands.
AD  - Oncode Institute, Utrecht, The Netherlands.
FAU - de Wit, Gijs F
AU  - de Wit GF
AD  - Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, 
      Amsterdam, The Netherlands.
AD  - Oncode Institute, Utrecht, The Netherlands.
FAU - Battaglia, Thomas W
AU  - Battaglia TW
AD  - Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, 
      Amsterdam, The Netherlands.
AD  - Oncode Institute, Utrecht, The Netherlands.
FAU - Gelderblom, Hans
AU  - Gelderblom H
AUID- ORCID: 0000-0001-9270-8636
AD  - Department of Medical Oncology, Leiden University Medical Center, Leiden, The 
      Netherlands.
FAU - Verheul, Henk M W
AU  - Verheul HMW
AD  - Department of Medical Oncology, Erasmus MC, Rotterdam, The Netherlands.
FAU - Schumacher, Ton N
AU  - Schumacher TN
AUID- ORCID: 0000-0003-0517-8804
AD  - Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, 
      Amsterdam, The Netherlands.
AD  - Oncode Institute, Utrecht, The Netherlands.
AD  - Department of Hematology, Leiden University Medical Center, Leiden, The 
      Netherlands.
FAU - Wessels, Lodewyk F A
AU  - Wessels LFA
AUID- ORCID: 0000-0002-1656-6995
AD  - Oncode Institute, Utrecht, The Netherlands.
AD  - Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, 
      The Netherlands.
AD  - Faculty of EEMCS, Delft University of Technology, Delft, The Netherlands.
FAU - Koning, Frits
AU  - Koning F
AD  - Department of Immunology, Leiden University Medical Center, Leiden, The 
      Netherlands.
FAU - de Miranda, Noel F C C
AU  - de Miranda NFCC
AUID- ORCID: 0000-0001-6122-1024
AD  - Department of Pathology, Leiden University Medical Center, Leiden, The 
      Netherlands. n.f.de_miranda@lumc.nl.
FAU - Voest, Emile E
AU  - Voest EE
AUID- ORCID: 0000-0001-8249-9586
AD  - Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, 
      Amsterdam, The Netherlands. e.voest@nki.nl.
AD  - Oncode Institute, Utrecht, The Netherlands. e.voest@nki.nl.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230111
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Immune Checkpoint Inhibitors)
RN  - 0 (Receptors, Antigen, T-Cell, gamma-delta)
RN  - 0 (beta 2-Microglobulin)
RN  - 0 (PDCD1 protein, human)
RN  - 0 (Receptors, KIR)
RN  - 0 (CTLA4 protein, human)
RN  - Turcot syndrome
SB  - IM
CIN - Nat Rev Immunol. 2023 Mar;23(3):137. PMID: 36726035
CIN - Nat Immunol. 2023 Mar;24(3):387-388. PMID: 36781987
CIN - Med. 2023 Mar 10;4(3):141-142. PMID: 36905925
MH  - Humans
MH  - *Colonic Neoplasms/drug therapy/genetics/immunology/therapy
MH  - *Histocompatibility Antigens Class I/genetics/immunology
MH  - *Immune Checkpoint Inhibitors/pharmacology/therapeutic use
MH  - *Immunotherapy
MH  - *Receptors, Antigen, T-Cell, gamma-delta/immunology
MH  - *T-Lymphocytes/immunology
MH  - beta 2-Microglobulin/deficiency/genetics
MH  - DNA Mismatch Repair/genetics
MH  - Receptors, KIR
MH  - Cell Line, Tumor
MH  - Organoids
MH  - Antigen Presentation
MH  - *Genes, MHC Class I/genetics
PMC - PMC9876799
COIS- M.C. has performed an advisory role or offered expert testimony for BMS, MSD and 
      NUMAB; has received honoraria from BMS and Roche; and has received financing of 
      scientific research from Roche, BMS and MSD. J.B.H. has received research funding 
      from BMS; and has performed an advisory role for BMS.
EDAT- 2023/01/12 06:00
MHDA- 2023/01/28 06:00
PMCR- 2023/01/11
CRDT- 2023/01/11 23:21
PHST- 2021/07/16 00:00 [received]
PHST- 2022/11/24 00:00 [accepted]
PHST- 2023/01/12 06:00 [pubmed]
PHST- 2023/01/28 06:00 [medline]
PHST- 2023/01/11 23:21 [entrez]
PHST- 2023/01/11 00:00 [pmc-release]
AID - 10.1038/s41586-022-05593-1 [pii]
AID - 5593 [pii]
AID - 10.1038/s41586-022-05593-1 [doi]
PST - ppublish
SO  - Nature. 2023 Jan;613(7945):743-750. doi: 10.1038/s41586-022-05593-1. Epub 2023 
      Jan 11.