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.
| Original language | English |
|---|---|
| Pages (from-to) | 743-750 |
| Number of pages | 8 |
| Journal | Nature |
| Volume | 613 |
| Issue number | 7945 |
| DOIs | |
| Publication status | Published - 26 Jan 2023 |
Bibliographical note
Funding Information: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.
Funding Information:
We thank K. C. M. J. Peeters, M. G. Kallenberg-Lantrua, D. Berends-van der Meer and F. A. Holman for their help in collecting and providing samples from patients with colon cancer; the staff at the Flow Cytometry Core Facility of the Leiden University Medical Center for their help with cell sorting; the staff at the Leiden Genome Technology Center for their help with scRNA-seq; M. Ganesh for help with cell culturing; D. Thommen for discussions; I. S. Rodriguez for the establishment of a B2M -knockout organoid line; L. Hoes for initial clinical findings; the staff at the Flow Cytometry Core Facility at the Netherlands Cancer Institute for their support; X. Kong for providing the lentiCRISPR plasmid for B2M knockout; the staff at Merus for providing anti-PD-1 antibodies for organoid experiments; and the staff at The Cancer Genome Atlas (TCGA) for providing data used in this manuscript. N.F.C.C.d.M. is funded by the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement no. 852832). E.E.V. received funding from the Oncode Institute and Open Targets (Identification of targets modulating lymphocyte-mediated tumour cell killing (project ID: OTAR2061); project leaders, M. Garnett and E.E.V.) and the Josephine Nefkens Foundation. F.K. was supported by the collaboration project TIMID (LSHM18057-SGF) financed by the PPP allowance made available by Top Sector Life Sciences & Health to Samenwerkende Gezondheidsfondsen (SGF) to stimulate public–private partnerships and co-financing by health foundations that are part of the SGF.
Funding Information:
We thank K. C. M. J. Peeters, M. G. Kallenberg-Lantrua, D. Berends-van der Meer and F. A. Holman for their help in collecting and providing samples from patients with colon cancer; the staff at the Flow Cytometry Core Facility of the Leiden University Medical Center for their help with cell sorting; the staff at the Leiden Genome Technology Center for their help with scRNA-seq; M. Ganesh for help with cell culturing; D. Thommen for discussions; I. S. Rodriguez for the establishment of a B2M-knockout organoid line; L. Hoes for initial clinical findings; the staff at the Flow Cytometry Core Facility at the Netherlands Cancer Institute for their support; X. Kong for providing the lentiCRISPR plasmid for B2M knockout; the staff at Merus for providing anti-PD-1 antibodies for organoid experiments; and the staff at The Cancer Genome Atlas (TCGA) for providing data used in this manuscript. N.F.C.C.d.M. is funded by the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement no. 852832). E.E.V. received funding from the Oncode Institute and Open Targets (Identification of targets modulating lymphocyte-mediated tumour cell killing (project ID: OTAR2061); project leaders, M. Garnett and E.E.V.) and the Josephine Nefkens Foundation. F.K. was supported by the collaboration project TIMID (LSHM18057-SGF) financed by the PPP allowance made available by Top Sector Life Sciences & Health to Samenwerkende Gezondheidsfondsen (SGF) to stimulate public–private partnerships and co-financing by health foundations that are part of the SGF.
Publisher Copyright:
© 2023, The Author(s).
