Human prostate cancer bone metastases have an actionable immunosuppressive microenvironment

Kfoury, Youmna; Baryawno, Ninib; Sévère, Nicolas; Mei, Shenglin; Gustafsson, Karin; Hirz, Taghreed; Brouse, Thomas; Scadden, Elizabeth W; Igolkina, Anna A.; Kokkaliaris, Konstantinos D.; Choi, Bryan D.; Barkas, Nikolas; Randolph, Mark A.; Shin, John H.; Saylor, Philip J.; Scadden, David T.; Sykes, David B.; Kharchenko, Peter V.

doi:10.1016/j.ccell.2021.09.005

Cited by 118 publications

(107 citation statements)

References 85 publications

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“…We hypothesized that the immunosuppressive myeloid cells were contributing to the exhausted T-cell phenotype, as our group has previously shown in the setting of metastatic prostate cancer (106). Indeed, there was a correlation between the MDSC and Treg activity signatures, pointing to the role of myeloid cells in establishing a T-cell suppressive and pro-tumor microenvironment.…”

Section: Discussionmentioning

confidence: 94%

Integrated single-cell and spatial transcriptomic analyses unravel the heterogeneity of the prostate tumor microenvironment

Hirz

Mei

Sarkar

et al. 2022

Preprint

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The treatment of primary prostate cancer delicately balances an active surveillance approach for low-risk disease with multimodal treatment including surgery, radiation therapy, and hormonal therapy for high-risk disease. Recurrence and development of metastatic disease remains a clinical problem, without a clear understanding of what drives immune escape and tumor progression. Here, we sought to comprehensively describe the tumor microenvironment of localized prostate cancer contrasting this with adjacent normal samples and healthy controls. We performed single-cell RNA sequencing and high-resolution spatial transcriptomic analysis. This revealed tumor context dependent changes in gene expression. Our data point towards an immune suppressive tumor microenvironment associated with suppressive myeloid populations and exhausted T-cells, in addition to high stromal angiogenic activity. We inferred cell-to-cell relationships at an unprecedented scale for ligand-receptor interactions within undissociated tissue sections. Our work provides a highly detailed and comprehensive resource of the prostate tumor microenvironment as well as tumor-stromal cell interactions.

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Section: Discussionmentioning

confidence: 94%

Integrated single-cell and spatial transcriptomic analyses unravel the heterogeneity of the prostate tumor microenvironment

Hirz

Mei

Sarkar

et al. 2022

Preprint

Self Cite

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“…Changes in homeostasis and function within the complex T cell networks may play a robust, multi-faceted role in dissemination of tumor cells to the bone marrow. For example, disruption of the CCL20-CCR6 axis prolonged survival and enhanced T cell reactivity in a syngeneic mouse model of metastatic PC [127]. Further research is needed to explore potentially actionable mechanisms to revert immune suppression and prevent invasion.…”

Section: Complex Multicellular Composition Of Bone and Bone Marrow Metastatic Nichesmentioning

confidence: 99%

“…CXCR4 was identified in lung and bone metastasis signatures in BC [258,259] and therefore could potentially modulate invasiveness to other metastatic sites. The CCR6-CCL20 pathway was identified in vertebral BM from patients with PC, and its inhibition prolonged survival in a murine model [127]. The CCL7-CCR3 axis promoted migration of PC cell lines towards human bone marrow-derived adipocytes and, of note, CCR3 expression was enriched in PC metastases to bone as compared to lymph node or visceral metastases [260].…”

Section: Chemokinesmentioning

confidence: 99%

“…The use of blanket tissue acquisition IRBs could facilitate collecting human specimens that would normally be discarded (for instance, following hip replacement surgery or orthopedic fixation of traumatic or osteoporotic fractures), and typically have minimal additional risk to the patient or donor. Recently the Boston BM Consortium established an integrated protocol to obtain bone marrow aspirate and tumor tissue from spinal metastases during spinal decompression surgeries for flow cytometry and single cell RNA-sequencing [127]. Collaborative labs could then establish a biobank of primary bone stromal cells from patients with solid tumors, hematologic malignancies, and donors without cancer.…”

Section: Future Directionsmentioning

confidence: 99%

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Advancing Treatment of Bone Metastases through Novel Translational Approaches Targeting the Bone Microenvironment

Sethakorn

Héninger

Sánchez-de-Diego

et al. 2022

Cancers

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Bone metastases represent a lethal condition that frequently occurs in solid tumors such as prostate, breast, lung, and renal cell carcinomas, and increase the risk of skeletal-related events (SREs) including pain, pathologic fractures, and spinal cord compression. This unique metastatic niche consists of a multicellular complex that cancer cells co-opt to engender bone remodeling, immune suppression, and stromal-mediated therapeutic resistance. This review comprehensively discusses clinical challenges of bone metastases, novel preclinical models of the bone and bone marrow microenviroment, and crucial signaling pathways active in bone homeostasis and metastatic niche. These studies establish the context to summarize the current state of investigational agents targeting BM, and approaches to improve BM-targeting therapies. Finally, we discuss opportunities to advance research in bone and bone marrow microenvironments by increasing complexity of humanized preclinical models and fostering interdisciplinary collaborations to translational research in this challenging metastatic niche.

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“…The tumor microenvironment can interfere with T cell trafficking and function, posing a crucial obstacle to personalized therapies. In very recent studies, the microenvironment of ovarian cancer [ 12 ] and prostate cancer bone metastases [ 13 ] was dissected using single-cell sequencing technologies, demonstrating the presence of monocytes and immature macrophages or inflammatory monocytes and M2 macrophages, respectively. In both cases, these immunosuppressive components can influence the T cell composition and dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Deciphering the Labyrinthine System of the Immune Microenvironment in Recurrent Glioblastoma: Recent Original Advances and Lessons from Clinical Immunotherapeutic Approaches

Anghileri

Patanè

Ianni

et al. 2021

Cancers

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The interpretation of the presence and function of immune infiltration in glioblastoma (GBM) is still debated. Over the years, GBM has been considered a cold tumor that is less infiltrated by effector cells and characterized by a high proportion of immunosuppressive innate immune cells, including GBM-associated microglia/macrophages (GAMs). In this context, the failure of checkpoint inhibitors, particularly in recurrent GBM (rGBM), caused us to look beyond the clinical results and consider the point of view of immune cells. The tumor microenvironment in rGBM can be particularly hostile, even when exposed to standard immunomodulatory therapies, and tumor-infiltrating lymphocytes (TILs), when present, are either dysfunctional or terminally exhausted. However, after checkpoint blockade therapy, it was possible to observe specific recruitment of adaptive immune cells and an efficient systemic immune response. In this review article, we attempt to address current knowledge regarding the tumor and immune microenvironment in rGBM. Furthermore, immunosuppression induced by GAMs and TIL dysfunction was revisited to account for genetic defects that can determine resistance to therapies and manipulate the immune microenvironment upon recurrence. Accordingly, we reevaluated the microenvironment of some of our rGBM patients treated with dendritic cell immunotherapy, with the goal of identifying predictive immune indicators of better treatment response.

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Human prostate cancer bone metastases have an actionable immunosuppressive microenvironment

Cited by 118 publications

References 85 publications

Integrated single-cell and spatial transcriptomic analyses unravel the heterogeneity of the prostate tumor microenvironment

Integrated single-cell and spatial transcriptomic analyses unravel the heterogeneity of the prostate tumor microenvironment

Advancing Treatment of Bone Metastases through Novel Translational Approaches Targeting the Bone Microenvironment

Deciphering the Labyrinthine System of the Immune Microenvironment in Recurrent Glioblastoma: Recent Original Advances and Lessons from Clinical Immunotherapeutic Approaches

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