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

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.

Exhausted intratumoral Vδ2− γδ T cells in human kidney cancer retain effector function

“…In this latter study, overall Vδ1 T-cell frequencies were not significantly different between tumor and healthy tissues. This later observation differs from our study in kidney cancer, where we observe a polarization towards enriched Vδ2 − in tumors versus healthy kidney tissue, in line with other studies showing Vδ2 − tumor reactivity in patients with colon cancer treated with checkpoint inhibition 52 . On the other hand, Wistuba and colleagues, among others, have shown the clinical relevance of bloodborne Vδ2 and not Vδ1 in response to anti-CTLA4 in patients with melanoma 53 , while in ovarian cancer, Foord and colleagues reported no apparent role in antitumor activity for Vδ1 T cells, which showed an exhausted-like phenotype and did not correlate with clinical benefit 54 .…”

Precision cancer medicine: Concepts, current practice, and future developments

“…Furthermore, data from the DRUP trial can lead to discoveries of novel disease (resistance) mechanisms and fuel basic research. An example of this is a recent published paper demonstrating the role of γ δ T cells in modulating the efficacy of cancer immunotherapy [145].…”

Organoids as an Enabler of Precision Immuno-Oncology

“…NK cells typically react to stress ligands via interactions including NKG2A–HLA-E and NKG2D–MIC-A/B [ 168 ], while γδ-T cells recognise phosphoantigens, such as exogenous zoledronic acid (ZOL), to exert cytotoxicity [ 169 ]. Strikingly, a recent study with ovarian cancer organoids shows that bi-specific PD-1/PD-L1 antibody activates NK cells in addition to CTLs [ 170 ], while another study with CRC organoids demonstrates the anti-tumour effect of ICIs from γδ-T cells (rather than αβ-T) when there is MHC-I defect on tumour cells [ 171 ], underlining their importance in I/O effectiveness. Organoid testing has also shown tumoricidal activity of γδ-T cells [ 172 ] and (CAR-)NK cells [ 173 ] for melanoma and mesothelioma, respectively.…”