The objective of the proposed Department of Defense (DoD) research project is to (1) study cancer immunosuppression during bone metastasis by using 3D immune-integrated vascularized bone tissue on a microfluidic chip that can simulate metastatic progress of cancer cells in bone at the cellular level, and (2) develop an innovative bone material that can deliver immunomodulatory agents to inhibit cancer immunosuppression in bone to increase the efficacy of anti-cancer immunotherapy and stabilize the weakened bone due to the metastatic cancer. Recently, we discovered that cancer cells cause immunosuppression by forming physical nanoscale bridges and hijacking energy sources (mitochondria) from immune cells. Mitochondria-gained cancer cells became metabolically empowered and grew faster while mitochondria-lost immune cells became metabolically impaired and exhibited decreased population. Strikingly, when we inhibited nanotube formation and mitochondria transfer between cancer cells and immune cells by using pharmacological inhibitor in tumor-bearing mice, the population of activated immune cells and anti-cancer efficacy of immunotherapy were significantly increased. Based on our strong preliminary study, we further aim to study the contribution of the energy-gained state of cancer cells on metastatic progress in bone and inhibit the energy trafficking of cancer cells from macrophages in bone to prohibit cancer metastasis and recurrence in bone.

The career goal of the Principal Investigator (PI) is to become an academic leader in the metastatic bone cancer field by developing next generation engineered immunotherapies. Through this DoD project, she will address the Fiscal Year 2020 (FY20) Peer Reviewed Cancer Research Program (PRCRP) Topics Areas “Metastatic cancers” and “Immunotherapy” by revealing the underlying pathological mechanism during cancer metastasis and immunosuppression and developing immunomodulatory materials that can be used to treat metastatic bone defects. She will also contribute to FY20 PRCRP Military Health Focus Area “Mission Readiness” by increasing the survival rate and quality of the life of the military patients with cancer metastasis in bone. The PI will bring her research knowledge and skillsets in bone materials, vascularized bone tissue engineering, biomedical devices, and organ-on-a-chip into the cancer field and closely work with other cancer immunologists to develop creative interdisciplinary engineered immunotherapies to defeat metastatic bone cancer.

This research project will significantly help patients with cancer metastasis in bone. Currently, bone metastasis is incurable, even though bone is the most prevalent metastatic sites for more than 70% of malignant cancers. Metastasis in bone significantly weakens the bone by disrupting tissue homeostasis and causing random assembly of bone minerals. As a result, bone gets easily fractured with routine movements, which causes devastating pain to patients. Due to this reason, the survival rate and the quality of life of patients with bone metastasis are extremely poor. The current therapies for treating bone metastasis are mostly focused on symptomatically treating bone pain as per World Health Organization guidelines, but bone pain is extremely difficult to treat, as it is resistive to pain medications such as opioids. Since the injection of bone cement at the metastatic fracture site can stabilize the weakened bone and reduce pain, currently, polymethylmethacrylate (PMMA) cement is widely used to stabilize bone structure based on its excellent mechanical strength. However, PMMA is plexiglass that does not integrate into the bone and thus can cause secondary cracks. Moreover, PMMA releases heat during its polymerization (>80 °C), which burns surrounding tissue. Our proposed immunomodulatory bone material will be made of bone minerals that already exist in the human body and deliver a pharmacological inhibitor to prohibit cancer immunosuppression to effectively promote bone regeneration, stabilize metastatic fractures, inhibit metastatic progression to reduce the pain of the patients, which will have immediate clinical relevance.

The proposed research will also benefit active duty Service members, Veterans, and other military beneficiaries, as military members have a higher rate of cancers that frequently metastasizes to bone, including breast cancers and prostate cancers, than civilians. Our proposed immunomodulatory bone cement can significantly increase the anti-cancer efficacy of the existing immunotherapy in the clinic by prohibiting nanotube-mediated cancer immune evasion in bone. In addition, our novel in vitro 3D immune-integrated vascularized bone chip can potentially incorporate patient cells to simulate metastatic progress and observe the immune response to test various combinations of immunomodulatory agents on chip to find the optimal anti-cancer treatment for the individual patient. Such an in vitro modeling system can significantly save the time and costs of the patients by reducing hospital visits that require frequent biopsy collecting or the use of complex medical instruments.