Bone metastases are a highly debilitating complication in more than 70% of patients with advanced breast and prostate cancer, causing fractures, nerve compression, hypercalcemia. Currently approved treatments fail to cure bone metastases or increase patient survival. Immunotherapies activating T cells to fight cancer cells are changing cancer treatment, causing a durable response in some patients. However, it remains unclear whether immunotherapy could benefit patients with bone metastases. The bone microenvironment combines various immunosuppressive factors that could limit its efficacy. Also, T cells could increase bone resorption releases pro-metastatic growth factors from the bone matrix that can increase cancer cell growth. Using syngeneic mouse models, our study revealed that bone metastases from 4T1 breast cancer contain tumor-infiltrating lymphocyte (TILs) and that their development is increased in normal mice compared to immunodeficient and T-cell depleted mice (x3.6 and x1.6, respectively, p<0.05). This effect seemed caused by the TILs in bone, as T-cell depletion did not affect bone metastases from RM-1 prostate cancer cells that lack TILs and increased the volume of 4T1 orthotopic tumors. T cells from bone metastases expressed the pro-osteoclastic genes Rankl and Tnfa, and increased osteoclast formation ex vivo and in vivo, at the tumor-bone interface, contributing to bone metastasis development. This pro-osteoclastic effect is specific to inactivated T cells, since activated T cells, secreting IFNγ and IL-4, actually suppressed osteoclastogenesis, which could benefit patients. We confirmed that T cells in bone metastases were not activated, as >85% of T cells lacked the activation marker CD69. In addition, T cells from 4T1 bone metastases could not be activated in ex vivo cultures confirming the presence of immunosuppressive factors in this microenvironment. 4T1 bone metastases were associated with an increase of polymorphonuclear- and monocytic-MDSCs, metabolically active as they produced elevated levels of ROS and NO, respectively. While effective in other models, the PDE-5 inhibitor sildenafil and the bisphosphonate zoledronic acid did not affect the levels of MDSCs in bone metastases or their production of ROS and NO. Seeking other therapeutic targets, we found that 80% of monocytic-MDSCs are PD-L1+ in bone, which could trigger T-cell suppression since 70% express its receptor, PD-1. Collectively, our findings identified a new mechanism by which suppressed T cells increase osteoclastogenesis and bone metastases, and also provide a rationale for using immune checkpoint inhibitors since T-cell activation would increase their anti-cancer and their anti-osteoclastic properties.
Citation Format: Danna L. Arellano, Patricia Juárez, Paloma S. Almeida-Luna, Felipe Olvera, Samanta Jiménez, Pierrick G. J. Fournier. Bone microenvironment-suppressed T cells increase osteoclast formation and the development of osteolytic bone metastases in mice [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P033.