By 2040, projections show that there will be about 2.4 million new cancer cases per year in the United States, a 29.5 percent increase over the current rate (1). Chimeric antigen receptor (CAR) T cell therapy and other immunotherapies harness the body's immune system to fight cancer. While these therapies have shown promise, sometimes patients do not respond to the medications. 

A research team from the German Cancer Research Centre led by immunologist Michael Platten discovered that activated T cells express the immunoglobulin superfamily ligand B7H6, which marks them for destruction by natural killer (NK) cells (2). This potentially explains why some T cell-based cancer immunotherapies can prove ineffective. Understanding how B7H6 hinders anti-tumor immune responses could lead to improved cancer immunotherapies.

NK cells and T cells have complementary roles in anti-tumor immunity. NK cells exhibit innate cytotoxic activity against cancer cells. T cells, on the other hand, belong to the adaptive immune system and require antigen presentation to become active and eliminate pathogens or tumor cells. 

“NK cells have a role in removing virus-infected T cells,” said Platten. “What is novel is that this is a very specific mechanism whereby NK cells suppress anti-tumor immune responses by directly interacting with tumor-specific T cells.”

Using flow cytometry, Platten and his team found that activated T cells upregulated B7H6 expression and that NK cells bound to B7H6 via their NKp30 receptor. Subsequent co-culture experiments with NK cells and B7H6-activated T cells showed reduced T cell viability compared to T cells not expressing B7H6. 

The researchers then decided to evaluate this interaction in vivo. 

“The key challenge is that this is one of the molecules where we don't have a mouse homolog,” said Platten of B7H6. Therefore, he and his team used an immunodeficient mouse model engrafted with human CD19-positive acute lymphoblastic leukemia cells. This established a tumor microenvironment that closely resembled the human tumor landscape. 

The researchers then administrated CD19-targeted CAR T cells to the mouse model, with some groups receiving them in the presence of NK cells and others without. Co-administration of CAR T and NK cells correlated with decreased mouse survival and higher tumor burden. This suggested that B7H6-mediated suppression of CAR T cell function by NK cells could hinder the effectiveness of CAR T cell therapy.

This is really a novel immune checkpoint on T cells that can or should be targeted. 
- Michael Platten, German Cancer Research Centre

Using CRISPR-Cas9 gene editing technology the researchers further investigated B7H6's role in hindering T cell activity. Activated CAR T cells lacking B7H6 displayed enhanced viability in co-cultures with NK cells compared to control CAR T cells. The researchers added these same B7H6-knockout CAR T cells to the immunodeficient mouse model, and they saw enhanced tumor elimination and a more remarkable persistence of CAR T cells within the tumor microenvironment. This suggested that manipulating B7H6 expression on CAR T cells could improve CAR T cell therapy's efficacy.

“The study is almost surprising in its simplicity,” said John Lindner, an immunologist at BioMed X who was not involved in the study. “The beauty of this is how it shows that the immune response to tumors really involves more than one single immune cell type.” He explained that treating cancer is often an arms race between the cancer cells and the immune system but that this new insight about B7H6 on activated T cells “gives us another tool in the box that we can leverage to help balance that arms race out again and tip the scales in favor of the immune system.”

Understanding how the patient’s immune system can hinder the efficacy of treatments is important. Platten and his team plan to engineer CAR T cells lacking B7H6 and other ligands that the immune system can degrade and to translate these findings into a first-in-human clinical trial. 

Platten added, “This is really a novel immune checkpoint on T cells that can or should be targeted.”

References

1. Garner, W.B. et al. Predicting future cancer incidence by age, race, ethnicity, and sex. J Geriatr Oncol  14, 101393 (2023).
2. Kilian, M. et al. The immunoglobulin superfamily ligand B7H6 subjects T cell responses to NK cell surveillance. Sci Immunol  9, eadj7970 (2024).