CD169+ macrophages are suggested to play a pivotal role in establishing anti‐tumor immunity. They capture dead tumor cell‐associated antigens and transfer their information to lymphocsytes, including ...CD8+ T cells, which is important for successful tumor suppression. This study aimed to determine the prognostic significance of CD169+ macrophages residing in the tumor‐draining lymph nodes from cases of bladder cancer. In this retrospective study, 44 bladder cancer patients who received radical cystectomy were examined. The abundance of CD169+ macrophages in the regional lymph nodes and the number of CD8+ T cells in the primary tumor were investigated by immunohistochemistry. A CD169 score was calculated based on the intensity of CD169 staining and the proportion of CD169+ macrophages, and the scores were compared to the patients’ clinicopathological parameters. A high CD169 score was significantly associated with low T stage and with a high number of CD8+ T cells infiltrating into the tumor. The group with high CD169 expression had significantly longer cancer‐specific survival than the group with low CD169 expression (5‐year cancer‐specific survival rate: 83.3% vs 31.3%). In a multivariate analysis, the CD169 score was identified as a strong and independent favorable prognostic factor for cancer‐specific survival. Our findings suggest that CD169+ macrophages in the lymph nodes enhance anti‐tumor immunity by expanding CD8+ T cells in bladder cancer. The CD169 score may serve as a novel marker for the evaluation of bladder cancer prognosis.
Dead tumor cells are delivered to draining lymph nodes via lymphatic vessel. CD169+ macrophages in the regional lymph nodes capture dead tumor cells and present the tumor antigen to CD8+ T cells. The activated CD8+ T cells travel to the bladder tumor and suppress their proliferation.
Abstract
We report here newly discovered
O
-linked-N-acetylglucosamine (
O
-GlcNAc) modification of histone H2A at Ser
40
(H2AS40Gc). The mouse genome contains 18 H2A isoforms, of which 13 have Ser
...40
and the other five have Ala
40
. The combination of production of monoclonal antibody and mass spectrometric analyses with reverse-phase (RP)-high performance liquid chromatography (HPLC) fractionation indicated that the
O
-GlcNAcylation is specific to the Ser
40
isoforms. The H2AS40Gc site is in the L1 loop structure where two H2A molecules interact in the nucleosome. Targets of H2AS40Gc are distributed genome-wide and are dramatically changed during the process of differentiation in mouse trophoblast stem cells. In addition to the mouse, H2AS40Gc was also detected in humans, macaques and cows, whereas non-mammalian species possessing only the Ala
40
isoforms, such as silkworms, zebrafish and
Xenopus
showed no signal. Genome database surveys revealed that Ser
40
isoforms of H2A emerged in Marsupialia and persisted thereafter in mammals. We propose that the emergence of H2A Ser
40
and its O-GlcNAcylation linked a genetic event to genome-wide epigenetic events that correlate with the evolution of placental animals.
Recent studies have indicated the clinical significance of tumor‐associated macrophages (TAM) in several malignant tumors including breast cancer. Although recent studies have focused on ...CD68‐positive or CD163‐positive TAM in breast cancer, no study has investigated the significance of CD204‐positive TAM in breast cancer. We found that CD204 expression on macrophages was evaluated following stimulation with the conditioned medium (CM) of breast cancer cell lines. Paraffin sections of 149 breast cancer samples which were diagnosed as invasive ductal carcinoma were immunohistochemically analyzed for CD68, CD163 and CD204 expression. The results of analyses indicated that a high number of CD204‐positive TAM was associated with worse clinical prognoses, including relapse‐free survival, distant relapse‐free survival and breast cancer‐specific survival; however, neither the numbers of CD68‐positive or CD163‐positive TAM were associated with clinical courses. Of the clinicopathological factors investigated, estrogen receptor, Ki‐67 index, hormone subtype, and histological grade were significantly related to the increased number of CD163‐positive and CD204‐positive TAM. These data indicate the clinical significance of CD204‐positive TAM in breast cancer progression and CD204 is a marker for predicting clinical prognosis in breast cancer.
CD204 is a independent prognostic factor in breast cancer patients.
Abstract
Ever since immune checkpoint inhibitors have been approved for anti-cancer therapy in several cancers, including triple-negative breast cancer, the significance of programmed death-1 ligand ...1 (PD-L1) expression in the tumor immune microenvironment has been a topic of interest. In the present study, we investigated the detailed mechanisms of PD-L1 overexpression on tumor-associated macrophages (TAMs) in breast cancer. In in vitro culture studies using human monocyte-derived macrophages, lymphocytes, and breast cancer cell lines, PD-L1 overexpression on macrophages was induced by the conditioned medium (CM) of activated lymphocytes, but not that of cancer cells. Granulocyte–macrophage colony-stimulating factor (GM-CSF) derived from activated lymphocytes was found to be involved in PD-L1 overexpression, in addition to interferon (IFN)-γ, via STAT3 pathway activation. Macrophages suppressed lymphocyte activation, and this inhibition was impaired by PD-1 blocking. The CM of activated lymphocytes also induced the overexpression of PD-L2, but GM-CSF did not affect PD-L2 expression. In the murine E0771 breast cancer model, anti-GM-CSF therapy did not affect PD-L1 expression on TAMs, and the mechanisms of PD-L1 expression on TAMs might differ between humans and mice. However, not only PD-L1, but also PD-L2 was overexpressed on TAMs in the E0771 tumor model, and their expression levels were significantly lower in the tumors in nude mice than in wild-type mice. Anti-PD-L1 antibody and anti-PD-L2 antibody synergistically inhibited E0771 tumor development. In conclusion, PD-L1 and PD-L2 were overexpressed on TAMs, and they potentially contributed to immunosuppression. The GM-CSF-STAT3 pathway is thought to represent a new mechanism of PD-L1 overexpression on TAMs in human breast cancer microenvironment.
The immune status of patients can impact on the clinical course of cancer. Lymph node (LN) macrophages play critical roles in anti-cancer immunity via the activation of cytotoxic T-lymphocytes ...(CTLs). In this study, the prognostic significance of CD169+ LN macrophages was examined in patients with breast cancer. For this purpose the number of CD169+ cells and their ratio relative to total macrophages (CD68+) in regional LNs (RLNs), as well as the number of CD8+ CTLs in tumor tissues, were investigated using immunohistochemistry of paraffin-embedded tissue samples from 146 patients with breast cancer. The association of these data with clinicopathological factors was then analyzed. The number of cells positive for the pan-macrophage marker CD68 remained relatively uniform, while the number of CD169+ cells varied across all cases. Moreover, a high density of CD169+ cells correlated with early clinical stage and no LN metastasis, while a higher CD169+ to CD68+ ratio was significantly associated with small tumor size and a low Ki-67+ rate. There was also a significant correlation between the number of CD8+ CTLs and that of CD169+ macrophages in high grade breast cancer cases with a Ki-67 index greater than 40%. However, neither the density nor the ratio of CD169+ cells, nor the density of CD8+ CTLs, were associated with relapse-free survival, distant relapse-free survival, or breast cancer-specific survival. These findings suggest that CD169+ macrophages in RLNs might be a useful marker for assessing clinical stage, including LN states, in patients with breast cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although LiNi0.5Co0.2Mn0.3O2 (NCM523) cathode active material (CAM) is considered to have application potential in sulfide-based all-solid-state batteries (ASSBs), CAM/solid electrolyte interfacial ...instability remains a significant limiting factor. To effectively improve the interfacial stability and long-term cycling performance, NCM523 cathode material was coated with LiNbO3 layers of different thicknesses and uniformity. As a result, the cycle performance was greatly enhanced by increasing the thickness and uniformity of the LiNbO3-coated layer. Our findings further demonstrate that a thick (≥9 nm) and uniform coated layer (surface without uncoated area) displays outstanding electrochemical performance, especially cycle stability (capacity retention of 85.1% after 300 cycles at 60 °C), indicating that this strategy is very effective for constructing high-performance NCM cathodes for sulfide-based ASSBs. Moreover, the performance improvement mechanism was investigated by electrochemical impedance spectroscopy (EIS) combined with XPS and TEM-EDX analysis. The findings reveal that controlling the thickness and uniformity of the coating material plays a crucial role in the effective suppression of interface side reactions and resultant performance degradation in NCM cathodes.
•Performance of LiNbO3-coated LiNi0.5Co0.2Mn0.3O2 in sulfide-based cells was studied.•LiNbO3 layer thickness & uniformity affected the cyclability of all-solid-state cells.•Thicker & more uniform layers suppressed electrode/electrolyte interfacial reactions.•Outstanding cycling capability was achieved at LiNbO3 layer thicknesses of ≥9 nm.•The adopted interface engineering strategy may be applied to other cathode materials.
Mitochondrial protein import requires cooperation of the machineries called translocators in the outer and inner mitochondrial membranes. Here we analyze the interactions of Tom22, a multifunctional ...subunit of the outer membrane translocator TOM40 complex, with other translocator subunits such as Tom20, Tom40, and Tim50 and with substrate precursor proteins at a spatial resolution of the amino acid residue by in vivo and in organello site-specific photocross-linking. Changes in cross-linking patterns caused by excess substrate precursor proteins or presequence peptides indicate how the cytosolic receptor domain of Tom22 accepts substrate proteins and how the intermembrane space domain of Tom22 transfers them to Tim50 of the inner-membrane translocator.
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