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

Natasja L. Vries, Joris Haar, Vivien Veninga, Myriam Chalabi, Marieke E. Ijsselsteijn, Manon Ploeg, Jitske Bulk, Dina Ruano, Jose G. Berg, John B. Haanen, Laurien J. Zeverijn, Birgit S. Geurts, Gijs F. Wit, Thomas W. Battaglia, Hans Gelderblom, Henk M. W. Verheul, Ton N. Schumacher, Lodewyk F. A. Wessels, Frits Koning, Noel F. C. C. Miranda () and Emile E. Voest ()
Additional contact information
Natasja L. Vries: Leiden University Medical Center
Joris Haar: Netherlands Cancer Institute
Vivien Veninga: Netherlands Cancer Institute
Myriam Chalabi: Netherlands Cancer Institute
Marieke E. Ijsselsteijn: Leiden University Medical Center
Manon Ploeg: Leiden University Medical Center
Jitske Bulk: Leiden University Medical Center
Dina Ruano: Leiden University Medical Center
Jose G. Berg: Netherlands Cancer Institute
John B. Haanen: Netherlands Cancer Institute
Laurien J. Zeverijn: Netherlands Cancer Institute
Birgit S. Geurts: Netherlands Cancer Institute
Gijs F. Wit: Netherlands Cancer Institute
Thomas W. Battaglia: Netherlands Cancer Institute
Hans Gelderblom: Leiden University Medical Center
Henk M. W. Verheul: Erasmus MC
Ton N. Schumacher: Netherlands Cancer Institute
Lodewyk F. A. Wessels: Oncode Institute
Frits Koning: Leiden University Medical Center
Noel F. C. C. Miranda: Leiden University Medical Center
Emile E. Voest: Netherlands Cancer Institute

Nature, 2023, vol. 613, issue 7945, 743-750

Abstract: 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 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.

Date: 2023
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DOI: 10.1038/s41586-022-05593-1

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