What is it about?
Immune checkpoint inhibitors (ICIs) are treatments that help the immune system recognize and attack cancer, but we still don’t fully understand how they change the behavior of different immune cells. One checkpoint of interest is HHLA2 (B7-H7), which many tumors use to protect themselves. Drugs that block the HHLA2–KIR3DL3 interaction are now in early clinical trials, yet little is known about how this pathway specifically impacts natural killer (NK) cells. In our work, we studied NK cells in detail to see how B7-H7 influences their activity. We grew NK cells together with cancer cells, some of which we engineered to overproduce B7-H7. Using advanced single-cell RNA sequencing, we created a dataset of over 100,000 individual cells, including more than 90,000 NK cells, giving us a detailed look at how these cells respond under different conditions. From this, we identified distinct NK cell subtypes and showed how their abundance, gene activity, and signaling pathways were altered by B7-H7. We also found new molecules and pathways that seem to either enhance or limit NK cell function, such as cytokines, growth factors, and regulators like amphiregulin, NKG7, and TXNIP. Importantly, when combined with antibodies that block B7-H7, NK cells showed improved activity against tumors.
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Why is it important?
This is important because not every patient responds to current immune checkpoint therapies, and we don’t yet know why. B7-H7 is a newer checkpoint that many tumors use to block immune attack, but its impact on natural killer (NK) cells hasn’t been well understood. By studying how B7-H7 changes the behavior of specific NK cell subsets, we can start to see which immune responses are turned off and which can be reactivated with blocking antibodies. This knowledge could help us predict which patients are most likely to benefit from B7-H7 targeted drugs and aid in the development of more effective cancer immunotherapies.
Perspectives
What is interesting about this research is seeing how B7-H7 influences not just the activity but the diversity of NK cells. Blocking this checkpoint can shift NK cell states in specific ways, revealing which subsets are most important for anti-tumor responses. Understanding these nuances could be key to predicting patient response and designing smarter, more targeted immunotherapies.
Deepthi Chowbene
Beth Israel Deaconess Medical Center
Read the Original
This page is a summary of: Abstract 3229: Investigating the transcriptomic signature of HHLA2-mediated suppression of NK cell activity, Cancer Research, April 2025, American Association for Cancer Research (AACR),
DOI: 10.1158/1538-7445.am2025-3229.
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