Research Theme 1: Understanding the self-recognition mechanism by dendritic cells (DCs)

The immune system comprises many types of cells that cooperate together to induce appropriate immune responses. In particular, dendritic cells (DCs) are classified as innate immune cells, which are located throughout the body. DCs capture samples (antigens) from their environment and present antigens on their surface. T cells check these antigens, and if T cells recognize them as foreign (or “non-self”), T cells will induce an immune response to foreign antigens. Therefore, the ability to distinguish self from non-self is a key characteristic of the immune system, and T cells undergo very selective training by dendritic cells to make sure they can make that distinction.

The cells in our body display several molecules on their surface that identify them as “self” to immune cells. One of these self-identifying molecules is CD47. It was known that if T cells lack CD47, they would be efficiently eliminated by other immune cells. However, various experiments with mice lacking CD47 failed to produce an indication of the molecular mechanism or which cells were responsible for the elimination. We generated genetically modified mice in which only T cells lack CD47 and clearly identified that DCs induce cell death of T cells lacking CD47. Not only does this, for the first time, shed light on the mechanism behind the disappearance of CD47-deficient T cells, but it also reveals a completely unexpected capability of dendritic cells. This result is totally novel because it was believed that CD47-deficient cells are engulfed by macrophages. We thus found an entirely emerging in which the body identifies missing-self cells, that is, cells lacking CD47 being killed directly by dendritic cells (Fig.1) (Komori et al., PNAS 2023).

Our finding not only provides new insights into the fundamental question of how DCs recognize self-cells but also the consequence if cells alter the expression of self-identifying molecules.This finding also suggests a new line of research, and we continue to elucidate the detailed mechanisms, their involvement in diseases, and the development of new therapies based on this mechanism.

Research Theme 2: Development of preclinical human disease models using humanized immune system mice

Gaining knowledge of human physiology and pathophysiology is often hampered by restricted access to human tissues or limited to performing in vitro assays. Furthermore, the development of novel therapeutics for cancer immunotherapy, autoimmune- and inflammatory diseases is tightly restrictedby the use of human samples before moving to clinical trials, which is generally slow and costly. HumanImmune System (HIS) mice - immunodeficient mice reconstituted with a human immune system – offerthe unique opportunity to comprehensively study human hematopoiesis, infectious diseases,autoimmunity, and anti-tumor immunity in vivo (Fig.2).

We have previously reported that therapeutics targeting SIRPα that inhibit its interaction with its ligand CD47 enhances phagocytosis of cancer cells by macrophages. Since SIRPα is highly expressed in human macrophages, therapeutics targeting human SIRPα could potentially serve as novel immunotherapies for various human cancers, in combination with other therapeutic antibodies (e.g. Rituximab, Trastuzumab). However, there has been no suitable preclinical tumor model to test the in vivo effects of therapeutics targeting human immune cells, particlularly human macrophages.

To address this issue, we have newly established an immunotherapy model using humanized immune system (HIS) mice that allows us to evaluate the effect of anti-human SIRPα antibodies against human B-cell lymphomass. We demonstrated significant therapeutic effect of human SIRPα antibodies with rituximab, which induces tumor cells phagocytosis and reprograming of human macrophages against human B cell lines as well as tumors isolated from lymphoma patients (PDX models) (Fig. 3) (Saito et al., Front Immunol 2023).

We currently continue to develop precilnical tumor models for understanding tumor biology as well as for evaluating cancer immunotherapy.

Research Theme 3: Development of novel cancer therapies using mesenchymal stem cells

Coming soon