Prognostic Role of Tumor Immune Microenvironment in Pleural Epithelioid Mesothelioma
Hely OllilaMikko I. MäyränpääLassi PaavolainenJuuso PaajanenKatja VälimäkiEva SutinenHenrik WolffJari RäsänenOlli KallioniemiMarjukka MyllärniemiIlkka IlonenTeijo Pellinen
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Abstract:
Pleural mesothelioma (MPM) is an aggressive malignancy with an average patient survival of only 10 months. Interestingly, about 5%-10% of the patients survive remarkably longer. Prior studies have suggested that the tumor immune microenvironment (TIME) has potential prognostic value in MPM. We hypothesized that high-resolution single-cell spatial profiling of the TIME would make it possible to identify subpopulations of patients with long survival and identify immunophenotypes for the development of novel treatment strategies.We used multiplexed fluorescence immunohistochemistry (mfIHC) and cell-based image analysis to define spatial TIME immunophenotypes in 69 patients with epithelioid MPM (20 patients surviving ≥ 36 months). Five mfIHC panels (altogether 21 antibodies) were used to classify tumor-associated stromal cells and different immune cell populations. Prognostic associations were evaluated using univariate and multivariable Cox regression, as well as combination risk models with area under receiver operating characteristic curve (AUROC) analyses.We observed that type M2 pro-tumorigenic macrophages (CD163+pSTAT1-HLA-DRA1-) were independently associated with shorter survival, whereas granzyme B+ cells and CD11c+ cells were independently associated with longer survival. CD11c+ cells were the only immunophenotype increasing the AUROC (from 0.67 to 0.84) when added to clinical factors (age, gender, clinical stage, and grade).High-resolution, deep profiling of TIME in MPM defined subgroups associated with both poor (M2 macrophages) and favorable (granzyme B/CD11c positivity) patient survival. CD11c positivity stood out as the most potential prognostic cell subtype adding prediction power to the clinical factors. These findings help to understand the critical determinants of TIME for risk and therapeutic stratification purposes in MPM.Keywords:
Immunophenotyping
CD163
CD11c
Immunophenotyping
Minimal Residual Disease
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Over the last 10 years, immunophenotyping of haematologic malignancies has become an indispensable diagnostic supplement to the classical morphological approach. Immunophenotyping of haematopoietic cells is performed with the use of a number of monoclonal antibodies (MOABs), which are directed specifically against structures of blood cells that become expressed at the different stages of differentiation and maturation. Cells to which the fluorescently labelled MOABs are directed can be recognised and measured using fluorescence microscopy or fluorescence flow cytometry. Many MOABs, fluorochromes and user-friendly flow cytometers have become available in the last 15 years, as a result of which immunophenotyping is now routinely applied in clinical practice. Immunophenotyping has the potential to classify leukaemias and other malignant lymphomas according to cell type and stage of maturation. This information is important for the establishment of the right diagnosis and prognosis, and for the optimal treatment choice. In a number of cases immunophenotyping provides information which cannot be obtained by simple morphological investigation. The immunophenotyping of blood and bone-marrow cells is also a sensitive method for detecting minimal residual disease after an apparent complete remission has been achieved.
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Background: Acute leukemia area a group of neoplastic disorders characterized by proliferation and accumulation of immature hematopoeitic cells in bone marrow, blood, and other tissues. The present study was conducted to have a detailed understanding of immunophenotyping profi le, the morphologic and immunophenotypic discrepancy and importance of immunophenotyping in diagnosis of acute leukemia. Objectives: To study immunophenotyping profi le in acute leukemia (acute myeloid leukemia [AML], acute lymphoid leukemia, and mixed lineage leukemia) and to study its importance in diagnosis. Materials and Methods: This study was performed in Medical College, Jabalpur. 160 patients diagnosed morphologically with AML, acute lymphoblastic leukemia and mixed lineage leukemia seen were included in the study. Results: Only in 73% cases of acute leukemia did fi nd similarity in morphological appearance and immunophenotyping. In remaining 27% cases morphological fi ndings did not correlate with immunophenotyping expression. Diagnosis in these 27% patients changed after immunophenotyping. Conclusions: It is imperative and absolutely essential to ascertain the lineage of leukemia by immunophenotyping before starting on treatment as more than 25% of patients would not respond or later relapse if treatment is initiated on morphological diagnosis.
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CD68
CD163
CD11c
Infiltration (HVAC)
Macrophage polarization
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Background: Acute leukaemia (AL) are a heterogenous group of haematological malignancy characterized by uncontrolled clonal proliferation of haematopoietic progenitor cells. Objectives: The study was conducted to have a detailed understanding of immunophenotyping profile, the frequency of discrepancy between bone marrow morphology and immunophenotyping and importance of immunophenotyping in diagnosis of acute leukaemia. Methods: This prospective type of observational study was carried out with an aim to correlate the immunophenotype with bone
marrow morphology and to see the discrepancy between this two in acute leukaemia. A total of 38 untreated acute leukemia patients attending in the Department of Haematology, Bangabandhu Sheikh Mujib Medical University, Dhaka, during the period from October 2016 to September 2017were included in this study. At first the morphological diagnosis was done. Then the immunophenotypic profile was compared. Result: Around eighty-two cases of acute leukaemia did find similarity with immunophenotyping and remaining 18.4% shows discrepancy. Diagnosis in this 18.4% changes after immunophenotyping. Aberrant phenotypes were detected in 20 (52.6%) samples among them 13 (34.21%) cases were AML, 3 (7.8%) cases were B-ALL and 4 (10.52%) cases were T-ALL. Significant relation was not found between aberrant marker and FAB subtypes. Conclusion: In acute leukaemia morphological appearance of bone marrow does not always match with immunophenotyping. It is therefore imperative and absolutely essential to ascertain the lineage of leukaemia by immunophenotyping before starting treatment.
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Primary melanoma ulceration is an unfavourable prognostic factor included in current staging systems. Yet, the immunological and molecular alterations responsible for this adverse outcome have not been fully elucidated.We aimed to identify immunological differences between ulcerated and non-ulcerated primary melanomas concerning both innate and adaptive immunity and to correlate these with clinical outcome.Formalin-fixed paraffin-embedded primary melanomas from 112 patients (pts) were analysed by immunohistochemistry. The expression of various markers identifying tumour-infiltrating lymphocytes, macrophages and dendritic cells was evaluated semi-quantitatively by three independent investigators. Tumour cell expression of programmed death-ligand 1 (PD-L1), transporter of antigen processing 1 and the MxA protein was also analysed.Recurrence occurred in 21/56 pts (37.5%) with ulcerated vs. 14/56 pts (25.0%) with non-ulcerated tumours (P = 0.15). Tumour ulceration was associated with more frequent development of brain metastasis (17.6 vs. 3.6% of pts, P = 0.015). Immunohistochemistry showed an association of ulceration with the presence of intratumoural CD68+ macrophages (P = 0.028) as well as with increased numbers of intratumoural CD11c+ dendritic cells (P = 0.014) and CD163+ macrophages (P = 0.001). PD-L1 positivity (expression in >1% of tumour cells) was more frequent in ulcerated than non-ulcerated tumours [40 (72.7%) vs. 25 (44.6%), P = 0.003]. A positive correlation between intratumoural CD11c+ (Spearman's correlation coefficient ρ: 0.42) and CD163+ (ρ: 0.31) cell count and frequency of tumour cell PD-L1 expression was detected.Our results confirm the adverse clinical outcome associated with primary melanoma ulceration, particularly concerning the risk of recurrence and subsequent development of brain metastases. The observed immunological differences suggest a conceivable role of increased intratumoural macrophage and dendritic cell counts associated with enhanced tumour cell PD-L1 expression potentially contributing to the immunosuppressive, growth-promoting microenvironment of ulcerated primary melanomas.
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Granulomatous slack skin (GSS) is an extremely rare subtype of cutaneous T-cell lymphoma accompanied by an abundant number of macrophages and is clinically characterized by the development of pendulous skin folds. However, the characteristics of these macrophages in GSS remain unclear. Here, we conducted a spatial transcriptomic study on one frozen GSS sample and drew transcriptomic maps of GSS for the first time. Gene expression analysis revealed the enrichment of three clusters with macrophage transcripts, each exhibiting distinct characteristics suggesting that their primary composition consists of different subpopulations of macrophages. The CD163+ /CD206+ cluster showed a tumor-associated macrophage (TAM) M2-like phenotype and highly expressed ZFP36, CCL2, TNFAIP6, and KLF2, which are known to be involved in T-cell interaction and tumor progression. The APOC1+ /APOE+ cluster presented a non-M1 or -M2 phenotype and may be related to lipid metabolism. The CD11c+ /LYZ+ cluster exhibited an M1-like phenotype. Notably, these cells strongly expressed MMP9, MMP12, CHI3L1, CHIT1, COL1A1, TIMP1, and SPP1, which are responsible for extracellular matrix (ECM) degradation and tissue remodeling. This may partially explain the symptoms of cutaneous relaxation in GSS. Further immunohistochemistry on four GSS cases demonstrated that CD11c predominantly marked granulomas and multinucleated giant cells, whereas CD163 was mainly expressed on scattered macrophages, appearing as a mutually exclusive pattern. The expression pattern of MMP9 overlapped with that of CD11c, implying that CD11c+ macrophages may be a source of MMP9. Our data shed light on the characteristics of macrophages in the GSS microenvironment and provide a theoretical basis for the application of MMP9 inhibitors to prevent cutaneous relaxation of GSS. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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MMP9
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This study aims to characterize the tumor microenvironment of plasmablastic lymphoma (PBL) in regard to the quantities of CD163(+) tumor associated macrophages (TAM) and PD1(+) tumor infiltrating lymphocytes (TIL). This article also reviews the existing knowledge of the role of PD-1/PD-L1 pathway in the tumor microenvironment of hematopoietic neoplasms, discusses potential mechanisms to explain our findings, and outlines areas for future studies. We performed CD163 and PD1 immunohistochemical studies in 11 cases classified as plasmablastic lymphoma, and recorded the percentages of positive TAMs and TILs. Based on previous studies, cut off values of ≥30% and >5% were used to classify the cases into high TAMs and TILs, respectively. We determined that the majority of cases (8 of 11, or 73%) had high percentage of TAMs, while only a minority had high percentage of TILs (3 of 11, or 27%). Our data shows a trend towards a negative correlation between TAMs and TILs (p=0.08), and a predominance of the pattern TAMhigh/TILlow (7 of 11, or 63%) compared to other patterns. The microenvironment of plasma-blastic lymphoma tends to show high percentage of TAMs (≥30%) combined with low percentage of TILs (≤5%). Additional studies are needed to determine the clinical significance of TILs and the influence of EBV and HIV infections on numbers of TILs in PBL. As high microenvironment TAMs have been associated with high microenvironment PD-L1 in other hematopoietic malignancies, our data supports the need for future studies on the expression of PD-L1 in PBL.
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Objective To study the relationship of immunophenotype and FAB phenotype and guide clinical analysis and treatment.Methods Cell morphology checking and immunophenotyping were performed at the same time for the 505 patients with leukemia,flow cytometry had used for immunophenotype,on the end the results had been analyzed to understand the relationship between the two phenotypes.Results ①Among the 505 cases of leukemia,there were AML(248)、ALL(200)、CML(18)、CLL(15)、HAL(14)、UAL(10) in FAB phenotype and AML(163)、Ly+AML(83)、ALL(108)、My+ALL(106)、HAL(32)、UAL(13) in immunophenotype.② In AML the accordance rate and part accordance rate of the two phenotypes was 61.3% and 30.2%.In ALL the accordance rate was and part accordance rate was 53% and 44.5%.In HAL the accordance rate was 42.9%.Conclusion Immunophenotype plays an important role to distinguish AML、ALL subtype、variants leukemia and HAL.Immunophenotyping was shaper and more accurate than FAB phenotype,and is a supplementary and correction,but it can not replace the FAB phenotype.Combination of both can improve the diagnostic accuracy.
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Background and aim: Immunophenotype analysis of lesional histiocytes in subacute necrotizing lymphadenitis (SNL) has revealed several unexpected findings. Histiocytes express myeloperoxidase (MPO), and immature dendritic cells occupy a significant proportion of the lesional cells in SNL. However, whether MPO-expressing lesional histiocytes of SNL also express immunophenotypic markers of immature dendritic cells has not been determined. Methods: The immunophenotypes of lesional histiocytes in paraffin-embedded tissue sections from 26 patients with SNL were analyzed using a panel of dendritic cell and macrophage markers. Double immunohistochemical staining was also performed to confirm coexpression of several markers. Results: CD11c-expressing histiocytes represented a major component of lesional cells (averaging 50.1% of the lesional area), surpassing CD163-positive histiocytes (averaging 32.0% of the lesional area). Double immunohistochemical staining confirmed that a significant proportion of CD11c-expressing histiocytes also coexpressed MPO as well as CD163. CD123-positive plasmacytoid dendritic cells (averaging 3.2% of the lesional area) were minor lesional cells, and fascin-positive mature dendritic cells were not present in the lesions. Conclusions: Our results demonstrate that the main lesional cells in SNL are histiocytes expressing myeloid dendritic cell and macrophage markers as well as MPO, indicating phenotypic plasticity and functional versatility of histiocyte lineage cells.
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Immunophenotyping
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