Tumor-derived exosomes, which are nanometer-sized extracellular vesicles of endosomal origin, have emerged as promoters of tumor immune evasion but their role in prostate cancer (PC) progression is poorly understood. In this study, we investigated the ability of prostate tumor-derived exosomes to downregulate NKG2D expression on natural killer (NK) and CD8+ T cells. NKG2D is an activating cytotoxicity receptor whose aberrant loss in cancer plays an important role in immune suppression. Using flow cytometry, we found that exosomes produced by human PC cells express ligands for NKG2D on their surface. The NKG2D ligand-expressing prostate tumor-derived exosomes selectively induced downregulation of NKG2D on NK and CD8+ T cells in a dose-dependent manner, leading to impaired cytotoxic function in vitro. Consistent with these findings, patients with castration-resistant PC (CRPC) showed a significant decrease in surface NKG2D expression on circulating NK and CD8+ T cells compared to healthy individuals. Tumor-derived exosomes are likely involved in this NKG2D downregulation, since incubation of healthy lymphocytes with exosomes isolated from serum or plasma of CRPC patients triggered downregulation of NKG2D expression in effector lymphocytes. These data suggest prostate tumor-derived exosomes as down-regulators of the NKG2D-mediated cytotoxic response in PC patients, thus promoting immune suppression and tumor escape.
Background Prostate cancer (PCa) is one of the most frequently diagnosed cancers in the world. Emerging evidence suggests that inflammatory cells such as M2 macrophages and regulatory T cells (T regs ) can contribute to cancer progression by suppressing the anti‐tumor immune response. This study investigated the number of CD163‐positive M2 macrophages in PCa tissue. It also investigated the correlation and interaction of M2 macrophages and T regs . Methods This nested case‐control study included subjects from a cohort of men diagnosed with PCa as an incidental finding during transurethral resection of the prostate. The cases were 225 men who died from PCa, and the controls were 367 men who survived more than 10 years after PCa diagnosis without disease progression. Infiltrating CD163‐positive M2 macrophages and FOXP3/CD4‐positive T regs in PCa tissue were identified using immunohistochemistry. The correlation and interaction of M2 macrophages and T regs were assessed using Spearman's rank‐order correlation and a likelihood test, respectively. Logistic regression was used to estimate odds ratios (ORs) for lethal PCa and macrophage counts. Results The number of M2 macrophages and T regs showed a significant correlation ( P < 0.001) but no interactions. The OR for lethal PCa was 1.93 (95%CI: 1.23‐3.03) for men with high numbers of M2 macrophages. Also for cases with uncertain outcome (GS categories 3 + 4 and 4 + 3) high numbers of M2 macrophages does predict a poorer prognosis. Conclusions Our data showed that men with high numbers of M2 macrophages in the prostate tumor environment had increased odds of dying of PCa. It is possible that M2 macrophages, together with other suppressor cells such as T regs , promote an immunosuppressive environment.
We studied heterogeneities at a molecular level in bone metastasis samples obtained from men with castration-resistant prostate cancer. We found differences of possible importance for therapy selection in individual patients.
Macrophage infiltration has been associated with an improved prognosis in patients with colorectal cancer (CRC), but a poor prognosis in prostate cancer (PC) patients. In this study, the distribution and prognostic value of proinflammatory M1 macrophages (NOS2+) and immunosuppressive M2 macrophages (CD163+) was evaluated in a cohort of 234 PC patients. We found that macrophages infiltrating PC were mainly of an M2 type and correlated with a more aggressive tumor and poor patient prognosis. Furthermore, the M1/M2 ratio was significantly decreased in PC compared to CRC. Using in vitro cell culture experiments, we could show that factors secreted from CRC and PC cells induced macrophages of a proinflammatory or immunosuppressive phenotype, respectively. These macrophages differentially affected autologous T lymphocyte proliferation and activation. Consistent with this, CRC specimens were found to have higher degrees of infiltrating T-helper 1 cells and active cytotoxic T lymphocytes, while PC specimens displayed functionally inactive T cells. In conclusion, our results imply that tumour-secreted factors from cancers of different origin can drive macrophage differentiation in opposite directions and thereby regulate the organization of the anti-tumour immune response. Our findings suggest that reprogramming of macrophages could be an important tool in the development of new immunotherapeutic strategies.
A role for regulatory lymphocytes has been demonstrated in the pathogenesis of type 1 diabetes in the NOD mouse but the nature of these cells is debated. CD1d-restricted NKT lymphocytes have been implicated in this process. Previous reports of reduced diabetes incidence in NOD mice in which the numbers of NKT cells are artificially increased have been attributed to the enhanced production of IL-4 by these cells and a role for classical NKT cells, using the Vα14-Jα18 rearrangement. We now show that overexpression in NOD mice of CD1d-restricted TCR Vα3.2+Vβ9+ NKT cells producing high levels of IFN-γ but low amounts of IL-4 leads to prevention of type 1 diabetes, demonstrating a role for nonclassical CD1d-restricted NKT cells in the regulation of autoimmune diabetes.
The NOD mouse is an important experimental model for human type 1 diabetes. T cells are central to NOD pathogenesis, and their function in the autoimmune process of diabetes has been well studied. In contrast, although recognized as important players in disease induction, the role of B cells is not clearly understood. In this study we characterize different subpopulations of B cells and demonstrate that marginal zone (MZ) B cells are expanded 2- to 3-fold in NOD mice compared with nondiabetic C57BL/6 (B6) mice. The NOD MZ B cells displayed a normal surface marker profile and localized to the MZ region in the NOD spleen. Moreover, the MZ B cell population developed early during the ontogeny of NOD mice. By 3 wk of age, around the time when autoreactive T cells are first activated, a significant MZ B cell population of adult phenotype was found in NOD, but not B6, mice. Using an F2(B6 × NOD) cross in a genome-wide scan, we map the control of this trait to a region on chromosome 4 (logarithm of odds score, 4.4) which includes the Idd11 and Idd9 diabetes susceptibility loci, supporting the hypothesis that this B cell trait is related to the development of diabetes in the NOD mouse.
Skeletal metastatic disease is a deleterious consequence of dissemination of tumor cells from numerous primary sites, such as prostate, lung and breast. Skeletal metastases are still incurable, resulting in development of clinical complications and decreased survival for cancer patients with metastatic disease. During the last decade, tumor cell-derived microvesicles have been identified and suggested to be involved in cancer disease progression. Whether cancer exosomes are involved in tumor and bone cell interactions in the metastatic site is still, however, a rather unexplored field. Here we show that exosomes isolated from the murine prostate cancer cell line TRAMP-C1 dramatically decrease fusion and differentiation of monocytic osteoclast precursors to mature, multinucleated osteoclasts. The presence of tumor cell-derived exosomes also clearly decreased the expression of established markers for osteoclast fusion and differentiation, including DC-STAMP, TRAP, cathepsin K, and MMP-9. In contrast, exosomes derived from murine fibroblastic cells did not affect osteoclast formation. Our findings suggest that exosomes released from tumor cells in the tumor-bone interface are involved in pathological regulation of bone cell formation in the metastatic site. This further strengthens the role of tumor cell-derived microvesicles in cancer progression and disease aggressiveness.
Based on gene-expression profiles, prostate tumors can be subdivided into subtypes with different aggressiveness and response to treatment. We investigated if similar clinically relevant subgroups can be identified simply by the combination of two immunohistochemistry markers: one for tumor cell differentiation (prostate specific antigen, PSA) and one for proliferation (Ki67). This was analyzed in men with prostate cancer diagnosed at transurethral resection of the prostate 1975–1991 (n = 331) where the majority was managed by watchful waiting. Ki67 and PSA immunoreactivity was related to outcome and to tumor characteristics previously associated with prognosis. Increased Ki67 and decreased PSA were associated with poor outcome, and they provided independent prognostic information from Gleason score. A combinatory score for PSA and Ki67 immunoreactivity was produced using the median PSA and Ki67 levels as cut-off (for Ki67 the upper quartile was also evaluated) for differentiation into subgroups. Patients with PSA low/Ki67 high tumors showed higher Gleason score, more advanced tumor stage, and higher risk of prostate cancer death compared to other patients. Their tumor epithelial cells were often ERG positive and expressed higher levels of ErbB2, phosphorylated epidermal growth factor receptor (pEGF-R) and protein kinase B (pAkt), and their tumor stroma showed a reactive response with type 2 macrophage infiltration, high density of blood vessels and hyaluronic acid, and with reduced levels of caveolin-1, androgen receptors, and mast cells. In contrast, men with PSA high/Ki67 low tumors were characterized by low Gleason score, and the most favorable outcome amongst PSA/Ki67-defined subgroups. Men with PSA low/Ki67 low tumors showed clinical and tumor characteristics intermediate of the two groups above. A combinatory PSA/Ki67 immunoreactivity score identifies subgroups of prostate cancers with different epithelial and stroma phenotypes and highly different outcome but the clinical usefulness of this approach needs to be validated in other cohorts.
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