Abstract
Bone marrow (BM) is a primary metastatic site in prostate cancer (PC) and bone invasion is considered incurable. T cell-mediated immune surveillance is essential in controlling both tumorigenesis and initiation of metastases. Beside tropism, dissemination of PC cells to the BM may be facilitated by defects in BM immune homeostasis predisposing this niche to colonization.To evaluate the BM immune microenvironment in locally advanced, non-metastatic PC, we performed flow cytometry analysis of myeloid and lymphoid subsets in BM aspirates and peripheral blood collected during prostatectomy. Healthy BM aspirates served to establish a reference range for comparison.We found alterations in BM immune composition of PC patients, including an increased CD4/CD8 ratio, enrichment of CD4+ T cells, increased CD56+CD3+ NKT and CD56+CD3- NK yields compared to healthy controls. The lymphoid phenotype remained comparable regarding T cell activation and chemokine receptor-based polarization patterns. Additionally, we found increased B7H3 expression in the myeloid monocyte/macrophage subset and decreased DC infiltration in BM of PC patients.These findings suggest that alterations in the immune milieu may limit immune surveillance that compromise the ability of the BM microenvironment to prevent tumor dissemination, and predispose development of bone metastases in a subset of patients with localized PC.
Highlights
The immune system provides critical protection against tumor progression and dissemination and can induce dramatic, even complete tumor regression in advanced stages of disease
In order to evaluate for alterations in the bone marrow (BM) immune microenvironment of men with primary, localized prostate cancer (PC), we developed two highly polychromatic flow cytometry assays to analyze and characterize the lymphoid and myeloid immune infiltrate within the BM
While the ability of PCs to subvert anti-tumor immunity in the BM has been well documented [25, 26], the immune landscape of bone invasion and the specific pathways that enable tumor cell survival within this immune-rich environment is still poorly understood partly due to the lack of in-depth reference data
Summary
The immune system provides critical protection against tumor progression and dissemination and can induce dramatic, even complete tumor regression in advanced stages of disease. Tumor reactive T cells in the BM have been shown to induce dramatic tumor regressions in an array of cancers and these T cells have even been found to be more potent than tumor reactive T cells in the peripheral circulation [12,13,14] Despite these potent anti-tumor properties, PC cells are able to disseminate to the BM with great frequency. The establishment and progression of PC metastases within this potentially hostile environment suggests that PC induces alterations in BM immune homeostasis, which permits survival of metastatic foci. Such alterations in the BM immune landscape, in men with early state, localized disease, have not yet been clearly defined
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