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- Title
The immunoglobulin superfamily ligand B7H6 subjects T cell responses to NK cell surveillance.
- Authors
Kilian, Michael; Friedrich, Mirco J.; Lu, Kevin Hai-Ning; Vonhören, David; Jansky, Selina; Michel, Julius; Keib, Anna; Stange, Saskia; Hackert, Nicolaj; Kehl, Niklas; Hahn, Markus; Habel, Antje; Jung, Stefanie; Jähne, Kristine; Sahm, Felix; Betge, Johannes; Cerwenka, Adelheid; Westermann, Frank; Dreger, Peter; Raab, Marc S.
- Abstract
Understanding the mechanisms that regulate T cell immunity is critical for the development of effective therapies for diseases associated with T cell dysfunction, including autoimmune diseases, chronic infections, and cancer. Co-inhibitory "checkpoint molecules," such as programmed cell death protein-1, balance excessive or prolonged immune activation by T cell–intrinsic signaling. Here, by screening for mediators of natural killer (NK) cell recognition on T cells, we identified the immunoglobulin superfamily ligand B7H6 to be highly expressed by activated T cells, including patient-infused CD19-targeting chimeric antigen receptor (CAR) T cells. Unlike other checkpoint molecules, B7H6 mediated NKp30-dependent recognition and subsequent cytolysis of activated T cells by NK cells. B7H6+ T cells were prevalent in the tissue and blood of several diseases, and their abundance in tumor tissue positively correlated with clinical response in a cohort of patients with immune checkpoint inhibitor–treated esophageal cancer. In humanized mouse models, NK cell surveillance via B7H6 limited the persistence and antitumor activity of CAR T cells, and its genetic deletion enhanced T cell proliferation and persistence. Together, we provide evidence of B7H6 protein expression by activated T cells and suggest the B7H6-NKp30 axis as a therapeutically actionable NK cell–dependent immune checkpoint that regulates human T cell function. Editor's summary: Natural killer (NK) cells can eliminate infected or malignant cells, but they are also believed to be capable of killing host immune cells. By screening NK cell ligands on human T cells, Kilian et al. found that the immunoglobulin superfamily ligand B7H6 promotes cytolysis of activated T cells by NK cells. In leukemia-bearing humanized mice, NK cells restricted the antitumor activity of chimeric antigen receptor (CAR) T cells in a B7H6-dependent manner. A higher ratio of intratumoral NK to T cells was associated with poor response to immune checkpoint inhibition in a cohort of patients with esophageal cancer. These findings demonstrate that B7H6 recognition by NK cells can restrict human antitumor T cell responses. —Claire Olingy
- Subjects
KILLER cells; T cells; AUTOIMMUNE diseases; CELL adhesion molecules; T cell receptors; CELLULAR recognition; IMMUNE checkpoint inhibitors; CANCER cells
- Publication
Science Immunology, 2024, Vol 9, Issue 95, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.adj7970