Research
The immune system protects our body by eliminating foreign substances such as pathogens as non-self. However, the mechanism to distinguish self and non-self is not perfect. If the immune response is not properly regulated, it can lead to chronic inflammation caused by autoimmune diseases and infection, and even tumor progression. In tumors, mutant proteins derived from tumor cells (cancer antigens) are targets of attack by the immune system as "non-self. Nevertheless, tumors can evade the immune attacks by inducing immunosuppression in the surrounding tissues or by reducing immunogenicity. It is becoming clear that the tumor microenvironment is established by the interaction of immune cells with not only cancer cells, but also with various tissue stromal cells such as mesenchymal cells and endothelial cells. We have study on the mechanisms underlying the pathogenesis of autoimmune diseases, skeletal diseases and cancer, by focusing on the crosstalk between immune cell and mesenchymal cells within the various tissues. We aim to understand the tumor-specific immune environment at the molecular level by unraveling the dynamic crosstalk among immune cells, tumor cells and various mesenchymal cells within the tumor tissues. The goal of our research is to develop innovative medical technologies for the prevention and treatment of cancer by controlling the immune environment of tumors focusing on the multicellular network.
Mechanisms underlying
the pathogenesis of
bone metastasis
Immune-centric network
in diseases
Mechanisms underlying
the pathogenesis of
bone metastasis
Recent advances in technologies for cancer screening have made it possible to detect cancer in its early stages, and therapeutic strategies such as anticancer agents and immunotherapy have contributed greatly to prolonging the lives of cancer patients. On the other hand, as the survival period of patients has been extended, problems related to cancer metastasis have emerged. Cancer metastasis become the biggest cause of death among cancer patients. In particular, bone is one of the typical target organs for metastasis, and bone metastasis causes bone pain, pathological fractures, paralysis due to spinal cord compression and other symptoms that directly affect quality of life (QOL), leading to a poor prognosis. However, it is still difficult to cure bone metastasis. Furthermore, there is no means of preventing bone metastasis from the primary tumor.
Bone is often thought of as a solid and static tissue, but in fact, its homeostasis is maintained by the breakdown of old bone tissue and its replacement with new bone. This process, called bone remodeling, is controlled by the optimal balance between bone formation by osteoblasts and bone resorption by osteoclasts. Osteoblasts are differentiated from mesenchymal stem cells, while osteoclasts belong to the hematopoietic/immune cell lineage. The TNF family cytokine RANKL is an essential factor for osteoclast differentiation. Pathologically, excess osteoclast activity leads to abnormal bone resorption, as seen in rheumatoid arthritis, periodontal disease, osteoporosis and bone tumors.
Bone is rich in growth factors and provides a fertile environment for cancer cells. When cancer cells metastasize to bone, they act on osteoblasts to increase the expression of RANKL, which in turn promotes bone resorption by osteoclasts. As a result, growth factors in the bone matrix are released, which act on the cancer cells to promote further tumor growth. "Tumor vicious cycle" organized by cancer cells, osteoblasts and osteoclasts is the basis of the pathogenesis of osteolytic bone metastases, which often occurs in lung cancer, breast cancer and so on. Now, a fully human anti-RANKL neutralizing antibody denosmab is used in the treatment of skeletal-related events by bone metastasis. On the other hand, RANKL is synthesized as a membrane-bound molecule, which is cleaved into the soluble form by proteases. On the other hand, RANKL is expressed on the plasma membrane as a membrane-bound form, and then produced in a soluble form by cleavage at the extracellular region. We found that membrane-bound RANKL, but not soluble RANKL, is important for physiological bone remodeling, postmenopausal osteoporosis and tumor-induced osteolysis. However, soluble RANKL has a distinct role in tumor metastasis to bone. Bone tissue-derived soluble RANKL promotes bone metastasis by exerting a chemotactic activity in tumor cells expressing RANK, suggesting that the attractant activity of soluble RANKL is one of the crucial mechanisms underlying the preferential metastasis of RANK+ tumor cells to bone (Asano, Okamoto et al, Nature Metab, 2019). Furthermore, we found that a novel RANKL small molecule inhibitor suppresses bone metastasis (Nakai, Okamoto et al, Bone Res 2019). It was reported that patients with high RANKL serum levels had a significantly increased risk of developing bone metastases (Rachner et al, Clin Cancer Res, 2019). Therefore, soluble RANKL may be effective as a serum biomarker for estimating the risk of developing bone metastases. Furthermore, RANKL inhibition with denosumab delayed bone metastasis in men with prostate cancer, suggesting the potential of targeting soluble RANKL as an effective therapeutic approach for bone metastases (reviewed in Okamoto, J Bone Miner Metab, 2021).
The bone marrow is the primary lymphoid organ that provides the environment for differentiation and maintenance of hematopoietic stem cells (HSCs) and immune progenitor cells. Notably, mesenchymal lineage cells build up the specialized microenvironment for the maintenance of HSC and the progeny. For example, LepR+CXCL12+ mesenchymal stem cells serve as the HSC niche with the high level of production of SCF and CXCL12, both of which are required for HSC maintenance and retention. Various pathogenic stimuli including inflammation to bone often have a significant impact on bone marrow hematopoiesis. We have previously shown that osteoblasts provide the niche for common lymphoid progenitors through IL-7 production, and that sepsis induced osteoblast loss in the bone marrow, resulting in lymphopenia (Terashima, Okamoto et al, Immunity, 2016). Immune cells including T cells are known to affect the differentiation and function of osteoclasts and osteoblasts (reviewed in Okamoto et al, Bone, 2023). Such pathological creosstalk between immune cells and bone are deeply involved in the pathogenesis of inflammation-associated bone diseases such as rheumatoid arthritis (see "Immune-centric network in diseases" below). In bone metastases, the bone marrow environment is profoundly altered by uncontrolled tumor progression. We are currently working to clarify the unique tumor microenvironment established by the multicellular network of immune, bone and tumor cells, in order to gain a more comprehensive understanding of the pathogenesis of metastasis and to develop cancer therapies.
Immune-centric network
in diseases
In autoimmune diseases, the interaction between the immune system and self-tissues produces a variety of biological reactions, chronic inflammation and tissue destruction. We have focused on helper T cells, which play a central role in immune responses, and have worked to elucidate a series of pathological processes from T cell activation to tissue destruction in autoimmune diseases. In rheumatoid arthritis, IL-17-producing helper T cells, Th17 cells, stimulate synovial fibroblasts to induce expression of RANKL, an essential factor for osteoclast differentiation, resulting in bone destruction (reviewed in Okamoto et al, Physiol Rev, 2017). The accumulation of inflammatory cells in the central nervous system, which are immune-privileged organs triggers chronic inflammation in multiple sclerosis. We have shown that RANKL on Th17 cells acts on astrocytes which support the blood brain barrier to induce chemokine CCL20 production, leading to inflammatory cell infiltration into the central nervous system (Guerrini, Okamoto et al, Immunity, 2015). In addition, we have also been studying on the transcriptional mechanism regulating Th17 cell development (Okamoto et al, Nature, 2010), novel cytokine signaling mechanisms essential for the maintenance and activation of peripheral CD4 T and CD8 T cells (Inoue, Okamoto et al, Immunity, 2015). These studies have provided new insights into the molecular basis for the development of treatments for chronic inflammatory diseases including autoimmune disorders.
The immune system is deeply involved in the process of tissue repair. For example, the interaction between immune cells and mesenchymal stem cells plays an important role in bone regeneration after fracture. We have shown that upon fracture, IL-17-producing γδ T cells immediately increase around the injured tissues, and that IL-17-producing γδ T cells enhance the osteogenesis by PDGFα+Sca1+ mesenchymal stem cell populations, leading to bone healing (Ono, Okamoto et al, Nature Commun, 2016). This is the first report of the role of γδ T cells in the musculoskeletal system. The findings would provide important insights into the understanding of the mechanisms underlying the pathogenesis of psoriatic arthritis and ankylosing spondylitis and disease control with IL-17-targeted drugs.
By investigating the molecular mechanism of T cell differentiation as well as the crosstalk between immune cells and various tissue cells, we aim to understand the pathogenetic mechanisms of diseases involving immune dysregulation. Furthermore, the establishment of novel regulatory approaches to immune responses will lead to the development of efficient strategies to induce anti-tumor immune responses.