Human prostate cancer bone metastases have an actionable immunosuppressive microenvironment

Abstract

Cancer-related mortality due to solid tumor malignancies is overwhelmingly due to the development and progression of metastases. In advanced prostate cancer, metastases most often involve the bone 1 and generally represent incurable disease. It remains unclear what aspects of the bone marrow microenvironment make it hospitable to metastatic dissemination. Similarly, the impact of the metastatic tumor on hematopoiesis and the marrow immune response is poorly understood. Here we take advantage of rare spinal cord decompression surgeries to profile marrow and metastatic tumors from men with advanced prostate cancer at single-cell resolution. We contrast the cellular composition and transcriptional states in matched samples of tumor and liquid bone marrow collected at adjacent vertebral body levels, as well as bone marrow of orthopedic patients without malignancy.Metastatic prostate cancer was associated with hematopoietic suppression and multifaceted immune distortion. There was exhaustion of specific T-cell subsets, appearance of inflammatory lymphocytes and macrophages, and alteration of cytokine profiles. The chemokine CCL20 was notably overexpressed by myeloid cells, as was its cognate CCR6 receptor on T-cells. This dual overexpression was associated with repressed immune responses. We used a syngeneic mouse model of bone-metastatic prostate cancer to explore this observation, and demonstrated that disruption of the CCL20-CCR6 axis resulted in significant prolongation of survival. Overall, comparative high-resolution analysis of bone marrow reveals distinct alterations associated with prostate cancer bone metastases that may be amenable to therapeutic targeting with the goal of altering cancer progression.3 ManuscriptProstate cancer frequently metastasizes to bone where, in the castration-resistant setting, 70 to 90% of patients have radiographically-detectable skeletal involvement 1-5 . To date, bone metastases represent a generally incurable form of prostate cancer and contribute significantly to disease-specific morbidity 6 . In particular, metastatic involvement of the spinal column can result in pathologic fracture and spinal cord compression leading to significant neurologic and functional disability. Surgical decompression/stabilization and targeted radiation are used selectively. Approved bone-targeted systemic therapies offer some benefit. Zoledronic acid and denosumab delay skeletal morbidity but do not improve overall survival 7 . The radiopharmaceutical radium-223 offers a modest improvement in overall survival 8 . The immune checkpoint therapies targeting CTLA4 and PD-1/PD-L1 have been unsuccessful in clinical trials in unselected prostate cancer populations 9 despite the high abundance of T lymphocytes in the tissue. In particular, emerging evidence indicates that patients with bone metastases are at a disadvantage when it comes to response to immune checkpoint therapies 10 .Altogether, this indicates that there is a clear need for new and more effective approaches for our patients with bone metast...

The Role of Cancer-Associated Fibroblasts in Prostate Cancer Tumorigenesis

“…Much of our knowledge derives from microarray analysis on laser capture microdissected tumor and stromal areas [164,165] and xenograft models [44], which allow distinction of the stroma, provided by the host organism, from the human tumor cells. Nevertheless, the recent development of techniques such as next generation sequencing and single cell-analysis is changing our understanding of the landscape of PCa reactive stroma in bone metastasis, as well as in primary PCa, in terms of the multi-omic molecular profiling and elucidation of cellular processes occurring in distinct stromal cell populations [58,60,166].…”

Selective vulnerability of supragranular layer neurons in schizophrenia

“…[4][5][6][7][8][9][10][11][12][13][14] for statistical analysis. To incorporate the unique effect of each donor on which multiple measurements were taken, we applied Linear Mixed Models (LMM) with random effect using the 'lme' function of 'nlme' package (16)(17)(18). The significance level was set to 1% (α=0.01).…”

“…S7A,B). As changes in proportion of one subtype could potentially skew the representation of other subtypes, we applied Compositional Data Analysis ( 18 ) techniques to calculate robust estimates of compositional changes (see Methods). This analysis confirmed that schizophrenia was linked to a general increase in most subtypes of L2_3_CUX2 and L4_5_FEZF2 families of principal neurons, and a decrease in several interneuron subtypes, most notable for SST_CALB1 (Fig.…”

A Subset of Localized Prostate Cancer Displays an Immunogenic Phenotype Associated with Losses of Key Tumor Suppressor Genes

“…Our analysis has so far primarily focused on infiltrating T cells, but the immune microenvironment clearly contains other elements, especially in advanced disease. Single-cell RNA sequencing of advanced PCa bone metastases has revealed depletion of B cells and an increase in M2-polarized tumor-associated macrophages (47). This is associated with increased exhaustion and decreased cytotoxicity programs in cytotoxic T lymphocytes in a CCR6-CCL20-dependent manner.…”