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Cancer Cell Jun 2024In acral melanoma (AM), progression from in situ (AMis) to invasive AM (iAM) leads to significantly reduced survival. However, evolutionary dynamics during this process...
In acral melanoma (AM), progression from in situ (AMis) to invasive AM (iAM) leads to significantly reduced survival. However, evolutionary dynamics during this process remain elusive. Here, we report integrative molecular and spatial characterization of 147 AMs using genomics, bulk and single-cell transcriptomics, and spatial transcriptomics and proteomics. Vertical invasion from AMis to iAM displays an early and monoclonal seeding pattern. The subsequent regional expansion of iAM exhibits two distinct patterns, clonal expansion and subclonal diversification. Notably, molecular subtyping reveals an aggressive iAM subset featured with subclonal diversification, increased epithelial-mesenchymal transition (EMT), and spatial enrichment of APOE/CD163 macrophages. In vitro and ex vivo experiments further demonstrate that APOECD163 macrophages promote tumor EMT via IGF1-IGF1R interaction. Adnexal involvement can predict AMis with higher invasive potential whereas APOE and CD163 serve as prognostic biomarkers for iAM. Altogether, our results provide implications for the early detection and treatment of AM.
Topics: Humans; Melanoma; Epithelial-Mesenchymal Transition; Skin Neoplasms; Antigens, Differentiation, Myelomonocytic; Antigens, CD; Neoplasm Invasiveness; Apolipoproteins E; Macrophages; Male; Female; Receptor, IGF Type 1; Tumor Microenvironment; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Spatial Analysis; Middle Aged; Prognosis; Disease Progression; Aged; Receptors, Cell Surface
PubMed: 38759655
DOI: 10.1016/j.ccell.2024.04.012 -
Frontiers in Oncology 2024Chronic myelomonocytic leukemia (CMML) is a rare hematological disorder characterized by variable risk of evolution to acute myeloid leukemia; to date, allogeneic stem...
Chronic myelomonocytic leukemia (CMML) is a rare hematological disorder characterized by variable risk of evolution to acute myeloid leukemia; to date, allogeneic stem cell transplantation is the only curative treatment. We report a case of choroidal involvement in a woman affected by CMML and presenting only with visual impairment. The patient was initially evaluated for an intensive therapeutic approach, but after biopsy the ocular lesion spontaneously regressed. Thus a "watch and wait" strategy was preferred. One year and a half after initial diagnosis, the patient is alive, with stable hematological disease and without any ocular involvement. Therefore, a close, not invasive follow up could be useful to tailor treatment for patients affected by single ocular lesions in CMML.
PubMed: 38756666
DOI: 10.3389/fonc.2024.1399894 -
Frontiers in Pharmacology 2024Current clinical research has reported the effectiveness and safety of venetoclax in combination with hypomethylating agents (VEN-HMA) in patients with myelodysplastic...
A real-world experience of venetoclax combined with hypomethylating agents vs. monotherapy hypomethylating agents in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia patients.
INTRODUCTION
Current clinical research has reported the effectiveness and safety of venetoclax in combination with hypomethylating agents (VEN-HMA) in patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Thus, this study aimed to examine the effectiveness and safety of VEN-HMA therapy in patients with MDS and CMML and compared its short-term and long-term therapeutic effects with HMA monotherapy.
METHOD
We analyzed data from our center, comprising 19 patients with MDS and CMML who received VEN-HMA therapy, compared to 32 patients treated with HMA monotherapy.
RESULTS
The overall response rate (ORR) in the VEN-HMA group was 73.7%, compared to 59.4% in the HMA group. The survival analysis revealed that the median overall survival (mOS) time in the VEN-HMA group was 16 months, with a median progression-free survival (mPFS) time of 9 months, both of which were longer than those observed in the HMA group ( < 0.05). Key adverse events (AEs) included grade 3-4 neutropenia (89.5% in VEN-HMA group vs. 87.5% in HMA group), grade 3-4 thrombocytopenia (73.7% vs. 71.9%), and anemia (73.7% vs. 90.6%). Infection of grade 3 or higher occurred in 63.2% of patients in the VEN-HMA group and 65.6% of patients in the HMA group.
DISCUSSION
Our study has confirmed the effectiveness and safety of the combined treatment of HMAs and venetoclax, which offers significant advantages to patients due to the relatively high and rapid response rates.
PubMed: 38756378
DOI: 10.3389/fphar.2024.1265840 -
Cell Reports. Medicine Jun 2024Acute myeloid leukemia (AML) is characterized by the accumulation of immature myeloid cells in the bone marrow and the peripheral blood. Nearly half of the AML patients...
Acute myeloid leukemia (AML) is characterized by the accumulation of immature myeloid cells in the bone marrow and the peripheral blood. Nearly half of the AML patients relapse after standard induction therapy, and new forms of therapy are urgently needed. Chimeric antigen receptor (CAR) T therapy has so far not been successful in AML due to lack of efficacy and safety. Indeed, the most attractive antigen targets are stem cell markers such as CD33 or CD123. We demonstrate that CD37, a mature B cell marker, is expressed in AML samples, and its presence correlates with the European LeukemiaNet (ELN) 2017 risk stratification. We repurpose the anti-lymphoma CD37CAR for the treatment of AML and show that CD37CAR T cells specifically kill AML cells, secrete proinflammatory cytokines, and control cancer progression in vivo. Importantly, CD37CAR T cells display no toxicity toward hematopoietic stem cells. Thus, CD37 is a promising and safe CAR T cell AML target.
Topics: Humans; Leukemia, Myeloid, Acute; Receptors, Chimeric Antigen; Animals; Immunotherapy, Adoptive; Mice; Tetraspanins; Cell Line, Tumor; T-Lymphocytes; Antigens, Differentiation, Myelomonocytic; Female; Male; Antigens, Neoplasm
PubMed: 38754420
DOI: 10.1016/j.xcrm.2024.101572 -
BMC Biotechnology May 2024β-TCP ceramics are versatile bone substitute materials and show many interactions with cells of the monocyte-macrophage-lineage. The possibility of monocytes entering...
β-TCP ceramics are versatile bone substitute materials and show many interactions with cells of the monocyte-macrophage-lineage. The possibility of monocytes entering microporous β-TCP ceramics has however not yet been researched. In this study, we used a model approach to investigate whether monocytes might enter β-TCP, providing a possible explanation for the origin of CD68-positive osteoclast-like giant cells found in earlier works.We used flow chambers to unidirectionally load BC, PRP, or PPP into slice models of either 2 mm or 6 mm β-TCP. Immunofluorescence for CD68 and live/dead staining was performed after the loading process.Our results show that monocytes were present in a relevant number of PRP and BC slices representing the inside of our 2 mm slice model and also present on the actual inside of our 6 mm model. For PPP, monocytes were not found beyond the surface in either model.Our results indicate the possibility of a new and so far neglected constituent in β-TCP degradation, perhaps causing the process of ceramic degradation also starting from inside the ceramics as opposed to the current understanding. We also demonstrated flow chambers as a possible new in vitro model for interactions between blood and β-TCP.
Topics: Monocytes; Ceramics; Calcium Phosphates; Humans; Bone Substitutes; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Porosity
PubMed: 38750469
DOI: 10.1186/s12896-024-00857-2 -
PloS One 2024Differentiation therapy using all-trans retinoic acid (ATRA) for acute promyelocytic leukemia (APL) is well established. However, because the narrow application and...
Differentiation therapy using all-trans retinoic acid (ATRA) for acute promyelocytic leukemia (APL) is well established. However, because the narrow application and tolerance development of ATRA need to be improved, we searched for another efficient myeloid differentiation inducer. Kinase activation is involved in leukemia biology and differentiation block. To identify novel myeloid differentiation inducers, we used a Kinase Inhibitor Screening Library. Using a nitroblue tetrazolium dye reduction assay and real-time quantitative PCR using NB4 APL cells, we revealed that, PD169316, SB203580, SB202190 (p38 MAPK inhibitor), and triciribine (TCN) (Akt inhibitor) potently increased the expression of CD11b. We focused on TCN because it was reported to be well tolerated by patients with advanced hematological malignancies. Nuclear/cytoplasmic (N/C) ratio was significantly decreased, and myelomonocytic markers (CD11b and CD11c) were potently induced by TCN in both NB4 and acute myeloid leukemia (AML) M2 derived HL-60 cells. Western blot analysis using NB4 cells demonstrated that TCN promoted ERK1/2 phosphorylation, whereas p38 MAPK phosphorylation was not affected, suggesting that activation of the ERK pathway is involved in TCN-induced differentiation. We further examined that whether ATRA may affect phosphorylation of ERK and p38, and found that there was no obvious effect, suggesting that ATRA induced differentiation is different from TCN effect. To reveal the molecular mechanisms involved in TCN-induced differentiation, we performed microarray analysis. Pathway analysis using DAVID software indicated that "hematopoietic cell lineage" and "cytokine-cytokine receptor interaction" pathways were enriched with high significance. Real-time PCR analysis demonstrated that components of these pathways including IL1β, CD3D, IL5RA, ITGA6, CD44, ITGA2B, CD37, CD9, CSF2RA, and IL3RA, were upregulated by TCN-induced differentiation. Collectively, we identified TCN as a novel myeloid cell differentiation inducer, and trials of TCN for APL and non-APL leukemia are worthy of exploration in the future.
Topics: Humans; Cell Differentiation; Leukemia, Promyelocytic, Acute; Myeloid Cells; CD11b Antigen; Cell Line, Tumor; HL-60 Cells; p38 Mitogen-Activated Protein Kinases; Leukemia, Myeloid, Acute; Imidazoles; Tretinoin; Pyridines; Proto-Oncogene Proteins c-akt
PubMed: 38743735
DOI: 10.1371/journal.pone.0303428 -
Medical Oncology (Northwood, London,... May 2024The impact of tumor microenvironment (TME) in influencing clinical response to first-line immune checkpoint inhibitor (ICI)-based treatment in advanced renal cell...
The impact of tumor microenvironment (TME) in influencing clinical response to first-line immune checkpoint inhibitor (ICI)-based treatment in advanced renal cell carcinoma (RCC) is unclear. Immunohistochemistry (IHC) could identify biomarkers related to immune checkpoints and immune cell population. This study retrospectively characterized TME from 28 RCC patients who received first line ICI-based therapy through IHC assessment of selected markers and explored preliminary evidence about their possible correlation with treatment efficacy. We found a significantly higher count of CD80+, CD163+ cells and their ratio in RCC with clear cell component compared to those without clear cell features; additionally, patients with metastatic disease at diagnosis were associated with higher expression of CD163+ cells, while higher count of CD4+ cells and CD4+/CD8+ ratio were found in RCC with sarcomatoid features. Patients achieving partial or complete response were associated with lower expression of CD163+ cells (median 28 vs 47; p = 0.049). Furthermore, lower expression of CD163+ was associated with better PFS (median PFS 20.0 vs 4.7 months; HR 0.22 p = 0.011) and OS (median OS NR vs 14.4 months; HR 0.28 p = 0.036). A longer OS was reported in PD-L1 CPS negative patients (median OS NR vs 11.8 months; HR 0.20 p = 0.024). High infiltration of CD163+ macrophages, who typically present "anti-inflammatory" M2-like phenotype, could identify a subgroup of patients with poor survival after receiving first-line ICI.
Topics: Humans; Carcinoma, Renal Cell; Tumor Microenvironment; Kidney Neoplasms; Male; Female; Middle Aged; Aged; Retrospective Studies; Immune Checkpoint Inhibitors; Adult; Immunotherapy; Receptors, Cell Surface; Antigens, CD; Biomarkers, Tumor; Aged, 80 and over; Treatment Outcome; Antigens, Differentiation, Myelomonocytic
PubMed: 38740647
DOI: 10.1007/s12032-024-02370-0 -
Archives of Dermatological Research May 2024Atopic dermatitis (AD) is an inflammatory skin disease with intense pruritus, and chronic skin colonization by Staphylococcus aureus. To understand the inflammatory...
Atopic dermatitis (AD) is an inflammatory skin disease with intense pruritus, and chronic skin colonization by Staphylococcus aureus. To understand the inflammatory status in AD, we investigated the inflammasome complex, that activates ASC (Apoptosis-associated speck-like protein containing a CARD), caspase-1 and GSDMD (gasdermin-D), and production of IL-1β and IL-18. We aimed to evaluate the expression of the inflammasome pathway in the skin of adults with AD. Thirty patients with moderate to severe AD and 20 healthy controls were enrolled in the study. We performed the analysis of the inflammasome components NLRP1, NLRP3, AIM-2, IL-1β, IL-18, Caspase-1, ASC, GSDMD, and CD68 expression (macrophage marker) by immunohistochemistry and immunofluorescence. The main findings included increased expression of NLRP3, NLRP1 and AIM-2 at dermal level of severe AD; augmented IL-18 and IL-1β expression at epidermis of moderate and severe patients, and in the dermis of severe AD; augmented expression of ASC, caspase-1 and GSDMD in both epidermis and dermis of moderate and severe AD. We detected positive correlation between caspase-1, GSDMD and IL-1β (epidermis) and caspase-1 (dermis) and AD severity; NLRP3, AIM-2 and IL-1β, and NLRP3 with IL-18 in the epidermis; ASC, GSDMD and IL-1β, and NLRP3, AIM-2, caspase-1, and IL-18 in the dermis. We also evidenced the presence of CD68 macrophages secreting GSDMD, ASC and IL-1β in moderate and severe AD. Cutaneous macrophages, early detected in moderate AD, have its role in the disease inflammatory mechanisms. Our study indicates a canonical activation pathway of inflammasomes, reinforced by the chronic status of inflammation in AD. The analysis of the inflammasome complex evidenced an imbalance in its regulation, with increased expression of the evaluated components, which is remarkably in severe AD, emphasizing its relevance as potential disease biomarkers and targets for immunomodulatory interventions.
Topics: Adult; Female; Humans; Male; Middle Aged; Young Adult; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Apoptosis Regulatory Proteins; CARD Signaling Adaptor Proteins; Case-Control Studies; Caspase 1; CD68 Molecule; Dermatitis, Atopic; DNA-Binding Proteins; Epidermis; Gasdermins; Inflammasomes; Interleukin-18; Interleukin-1beta; Intracellular Signaling Peptides and Proteins; Macrophages; NLR Family, Pyrin Domain-Containing 3 Protein; NLR Proteins; Phosphate-Binding Proteins; Severity of Illness Index; Skin
PubMed: 38734816
DOI: 10.1007/s00403-024-02899-0 -
Journal of Translational Medicine May 2024The immune microenvironment impacts tumor growth, invasion, metastasis, and patient survival and may provide opportunities for therapeutic intervention in pancreatic...
BACKGROUND
The immune microenvironment impacts tumor growth, invasion, metastasis, and patient survival and may provide opportunities for therapeutic intervention in pancreatic ductal adenocarcinoma (PDAC). Although never studied as a potential modulator of the immune response in most cancers, Keratin 17 (K17), a biomarker of the most aggressive (basal) molecular subtype of PDAC, is intimately involved in the histogenesis of the immune response in psoriasis, basal cell carcinoma, and cervical squamous cell carcinoma. Thus, we hypothesized that K17 expression could also impact the immune cell response in PDAC, and that uncovering this relationship could provide insight to guide the development of immunotherapeutic opportunities to extend patient survival.
METHODS
Multiplex immunohistochemistry (mIHC) and automated image analysis based on novel computational imaging technology were used to decipher the abundance and spatial distribution of T cells, macrophages, and tumor cells, relative to K17 expression in 235 PDACs.
RESULTS
K17 expression had profound effects on the exclusion of intratumoral CD8+ T cells and was also associated with decreased numbers of peritumoral CD8+ T cells, CD16+ macrophages, and CD163+ macrophages (p < 0.0001). The differences in the intratumor and peritumoral CD8+ T cell abundance were not impacted by neoadjuvant therapy, tumor stage, grade, lymph node status, histologic subtype, nor KRAS, p53, SMAD4, or CDKN2A mutations.
CONCLUSIONS
Thus, K17 expression correlates with major differences in the immune microenvironment that are independent of any tested clinicopathologic or tumor intrinsic variables, suggesting that targeting K17-mediated immune effects on the immune system could restore the innate immunologic response to PDAC and might provide novel opportunities to restore immunotherapeutic approaches for this most deadly form of cancer.
Topics: Humans; Keratin-17; Pancreatic Neoplasms; Tumor Microenvironment; Female; Carcinoma, Pancreatic Ductal; Male; CD8-Positive T-Lymphocytes; Macrophages; Middle Aged; Aged; Receptors, Cell Surface; Antigens, Differentiation, Myelomonocytic; Antigens, CD
PubMed: 38730319
DOI: 10.1186/s12967-024-05252-1 -
Experimental and Molecular Pathology Jun 2024Soluble CD163 (sCD163) is a selective marker of macrophages whose circulating levels have been found to be induced in patients with active inflammatory bowel disease...
Soluble CD163 (sCD163) is a selective marker of macrophages whose circulating levels have been found to be induced in patients with active inflammatory bowel disease (IBD). Urinary proteins are emerging as non-invasive diagnostic biomarkers, and here, sCD163 levels were measured in the urine of 18 controls and 63 patients with IBD by enzyme-linked immunosorbent assay. Urinary sCD163 levels did, however, not differentiate IBD patients from controls. Analysis of sCD163 in the serum of 51 of these patients did not show higher levels in IBD. Primary sclerosing cholangitis (PSC) is often associated with IBD, and sCD163 was higher in the urine of the 21 patients and in the serum of the 13 patients with PSC compared to patients with IBD. Of clinical relevance, urinary sCD163 levels were higher in PSC patients compared to those with other chronic liver diseases (n = 16), while serum sCD163 levels were comparable between the two groups. Serum sCD163 of IBD and PSC patients positively correlated with serum C-reactive protein. Serum creatinine and glomerular filtration rate, surrogate markers for renal function, did not significantly correlate with urinary or serum sCD163 levels in IBD or PSC patients. Moreover, urinary sCD163 was not related to fecal calprotectin levels whereas serum sCD163 of IBD patients showed a positive trend. PSC associated with IBD and PSC without underlying IBD had similar levels of urinary sCD163 while serum sCD163 tended to be higher in the latter group. In PSC patients, urinary sCD163 did not correlate with serum aminotransferase levels, gamma glutamyl transferase, alkaline phosphatase, bilirubin or the Model for End Stage Liver Disease score. Ursodeoxycholic acid was prescribed to our PSC patients and fecal levels of ursodeoxycholic acid and its conjugated forms were increased in PSC compared to IBD patients. Otherwise, fecal bile acid levels of IBD and PSC patients were almost identical, and were not correlated with urinary and serum sCD163 in PSC. In summary, our study identified urinary sCD163 as a potential biomarker for PSC.
Topics: Humans; Antigens, Differentiation, Myelomonocytic; Cholangitis, Sclerosing; Antigens, CD; Receptors, Cell Surface; Biomarkers; Male; Female; Middle Aged; Adult; Inflammatory Bowel Diseases; Aged; C-Reactive Protein; Leukocyte L1 Antigen Complex
PubMed: 38729058
DOI: 10.1016/j.yexmp.2024.104900