A potential new treatment for angioimmunoblastic T-cell lymphoma?

A type of blood cell cancer called angioimmunoblastic T-cell lymphoma (AITL) can develop when mutations accumulate in stem cells with age, which T cells develop in the blood.

However, the underlying mechanism by which AITL develops was unknown. Now a team from the University of Tsukuba in Japan has shown that B cells, another type of blood cell, accumulate mutations in genes that control how the genetic material is packaged in the cell. These aberrant B cells then interact with T cells and lead to the development of AITL.

paper, “Clonal germinal center B cells function as a niche for T-cell lymphoma“, published in the magazine Blood.

ACH Cancer Communication

Blood cells such as B cells and T cells, which are involved in immunity, develop from stem cells in the bone marrow. Sometimes mutations occur in individual stem cells that cause the mutant stem cell to produce an increased output of blood cells, all of which carry identical mutations.

The likelihood of this increases with age, known as age-related clonal hematopoiesis, or ACH. ACH is known to be associated with various types of cancer. AITL, a T-cell cancer, is associated with ACH with mutations in a gene called TET2. The team used mouse models and human samples to show that the TET2 mutation must be present in all blood cells, not just T cells, for the mouse model to develop AITL.

Using single-cell RNA sequencing, a technique that can show which genes are active in just one cell, they were able to profile the immune cells present in the samples. This showed a significant increase in the number of aberrant “germinal center B cells”, a type of B cell with activation and proliferative capacity. These B cells show periodic mutations in the genes for the histone proteins, which organize the genetic material in the cell into higher structures. They also showed changes in the pattern of DNA modification, called methylation, which affects the genes expressed in the cell.

B cells and T cells can interact through molecules on the surface of the cells known as CD40 and CD40 ligand.

A potentially new approach

“Analysis of single-cell sequencing data identified this interaction between CD40 and CD40 ligand as potentially important in mediating crosstalk between aberrant B cells and tumor cells,” said lead author Manabu Fujisawa.

“Most importantly, the survival of mice with AITL can be prolonged by treatment with antibodies designed to inhibit the CD40 ligand,” said lead author Mamiko Sakata-Yanagimoto.

“Genes expressed in aberrant mouse GCB cells are also expressed in human AITL cells with TET2 mutations.”

This means that anti-CD40 ligand antibodies could potentially be a new therapeutic approach for human AITL.