Targeting HHLA2 (B7-H7) reveals subset-specific transcriptional changes in NK cells

What is it about?

Immune checkpoint inhibitors (ICIs) are drugs that help the immune system fight cancer, but we don’t fully understand how they change the behavior of immune cells. One checkpoint of interest is HHLA2 (also called B7-H7), which is found on many tumors. HHLA2 can either activate or shut down immune cells, depending on which receptor it binds. One of its key partners is KIR3DL3, an inhibitory receptor found on both T cells and natural killer (NK) cells. We developed antibodies that specifically block the “off switch” interaction between HHLA2 and KIR3DL3, and these antibodies are now being tested in early-phase clinical trials for cancer. To study how blocking this pathway affects immune cells, we used single-cell RNA sequencing on NK cells grown together with cancer cells that express HHLA2. Some cultures were treated with our HHLA2-blocking antibodies, while others received a control treatment. We found that NK cells could be grouped into different subtypes, each marked by specific molecules like XCL2 or CCL4, and that these subtypes responded differently when the HHLA2 “off switch” was blocked. For example, certain subsets became more abundant and showed changes in genes linked to important immune functions such as killing cancer cells, signaling to other immune cells, and producing cytokines. These results suggest that blocking HHLA2:KIR3DL3 doesn’t just “turn NK cells back on”—it reshapes the landscape of NK cell activity. Our next step is to see if these same NK cell subsets appear in tumors, which could help explain why some patients benefit more than others from therapies that target this pathway. In the long run, understanding these effects could guide us in selecting the patients most likely to respond to HHLA2-targeted treatments.

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Photo by National Institute of Allergy and Infectious Diseases on Unsplash

Photo by National Institute of Allergy and Infectious Diseases on Unsplash

Why is it important?

This work matters because not all patients respond to current immune checkpoint therapies, and we don’t fully understand why. HHLA2 is a newer checkpoint that tumors use to hide from the immune system, and by blocking it, we may be able to “wake up” immune cells that were otherwise turned off. Our findings show that blocking HHLA2 doesn’t just make NK cells more active; it actually changes the types of NK cells present and how they function. This could help explain why some patients respond better than others and may give us clues for predicting who will benefit from HHLA2-targeted treatments. In the bigger picture, this research brings us closer to more personalized and effective cancer immunotherapies.

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