NKG2A expression identifies a subset of human Vδ2 T cells exerting the highest antitumor effector functions
Valentina Cazzetta1, Elena Bruni1, Sara Terzoli2
1Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy; Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy.
Abstract:
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.
Insights
Human Vδ2 T cells with NKG2A show enhanced anti-cancer activity. Blocking this interaction releases their tumor-fighting potential, offering new cancer therapy strategies.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Human Vδ2 T cells are innate-like immune cells crucial for anti-tumor surveillance.
- A subset of Vδ2 T cells constitutively expresses NKG2A, indicating heightened responsiveness to cancer.
- NKG2A+ and NKG2A- Vδ2 T cells represent distinct developmental lineages with self-renewal capacity.
Purpose of the Study:
- To investigate the role of NKG2A expression in Vδ2 T cell anti-tumor activity.
- To explore the inhibitory mechanism of HLA-E on NKG2A+ Vδ2 T cells.
- To assess the therapeutic potential of targeting the NKG2A-HLA-E axis in various cancers.
Main Methods:
- Transcriptomic profiling to differentiate NKG2A+ and NKG2A- Vδ2 T cell populations.
- Functional assays to evaluate effector functions of Vδ2 T cells.
- Analysis of NKG2A-HLA-E checkpoint engagement in patient tumor samples.
Main Results:
- NKG2A+ Vδ2 T cells exhibit intrinsic hyper-responsiveness against cancer.
- Tumor cells expressing HLA-E counteract Vδ2 T cell activity via NKG2A-mediated inhibition.
- Masking or knocking out NKG2A restores Vδ2 T cell effector functions against HLA-E+ tumors.
- NKG2A-HLA-E checkpoint engagement correlates with patient survival in hepatocellular carcinoma, glioblastoma, and non-small cell lung cancer.
Conclusions:
- NKG2A expression defines a subset of hyper-responsive Vδ2 T cells with significant anti-cancer potential.
- The NKG2A-HLA-E axis represents a critical tumor immune evasion strategy.
- Targeting the NKG2A-HLA-E checkpoint offers a promising therapeutic avenue for combined cellular and immunologic anticancer therapies.
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