NKG2A expression identifies a subset of human Vδ2 T cells exerting the highest antitumor effector functions

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

NKG2A expression identifies a subset of human Vδ2 T cells exerting the highest antitumor effector functions

2021

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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