NKG2A expression identifies a subset of human Vδ2 T cells exerting the highest antitumor effector functions
2021
Valentina Cazzetta | Elena Bruni | Sara Terzoli | Claudia Carenza | Sara Franzese | Rocco Piazza | Paolo Marzano | Matteo Donadon | Guido Torzilli | Matteo Cimino | Matteo Simonelli | Lorenzo Bello | Anna Villa | Likai Tan | Sarina Ravens | Immo Prinz | Domenico Supino | Federico S. Colombo | Enrico Lugli | Emanuela Marcenaro | Eric Vivier | Silvia Della Bella | Joanna Mikulak | Domenico Mavilio
Summary: Human Vδ2 cells are innate-like γδ T effectors performing potent immune surveillance against tumors. The constitutive expression of NKG2A identifies a subset of Vδ2 T cells licensed with an intrinsic hyper-responsiveness against cancer. Indeed, the transcriptomic profiles of NKG2A+ and NKG2A− cells characterize two distinct “intralineages” of Vδ2 T lymphocytes that appear early during development, keep their phenotypes, and show self-renewal capabilities in adult life. The hyper-responsiveness of NKG2A+ Vδ2 T cells is counterbalanced by the inhibitory signaling delivered by human leukocyte antigen E (HLA-E) expressed on malignant cells as a tumor-escape mechanism. However, either masking or knocking out NKG2A restores the capacity of Vδ2 T cells to exert the highest effector functions even against HLA-E+ tumors. This is highly relevant in the clinic, as the different degrees of engagement of the NKG2A-HLA-E checkpoint in hepatocellular carcinoma, glioblastoma, and non-small cell lung cancer directly impact patients’ overall survival. These findings open avenues for developing combined cellular and immunologic anticancer therapies.
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