| 1. |
- La Fleur, Linnea, et al.
(author)
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Expression of scavenger receptor MARCO defines a targetable tumor-associated macrophage subset in non-small cell lung cancer
- 2018
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In: International Journal of Cancer. - : WILEY. - 0020-7136 .- 1097-0215. ; 143:7, s. 1741-1752
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Journal article (peer-reviewed)abstract
- Tumor-associated macrophages (TAMs) are attractive targets for immunotherapy. Recently, studies in animal models showed that treatment with an anti-TAM antibody directed against the scavenger receptor MARCO resulted in suppression of tumor growth and metastatic dissemination. Here we investigated the expression of MARCO in relation to other macrophage markers and immune pathways in a non-small cell lung cancer (NSCLC) cohort (n=352). MARCO, CD68, CD163, MSR1 and programmed death ligand-1 (PD-L1) were analyzed by immunohistochemistry and immunofluorescence, and associations to other immune cells and regulatory pathways were studied in a subset of cases (n=199) with available RNA-seq data. We observed a large variation in macrophage density between cases and a strong correlation between CD68 and CD163, suggesting that the majority of TAMs present in NSCLC exhibit a protumor phenotype. Correlation to clinical data only showed a weak trend toward worse survival for patients with high macrophage infiltration. Interestingly, MARCO was expressed on a distinct subpopulation of TAMs, which tended to aggregate in close proximity to tumor cell nests. On the transcriptomic level, we found a positive association between MARCO gene expression and general immune response pathways including strong links to immunosuppressive TAMs, T-cell infiltration and immune checkpoint molecules. Indeed, a higher macrophage infiltration was seen in tumors expressing PD-L1, and macrophages residing within tumor cell nests co-expressed MARCO and PD-L1. Thus, MARCO is a potential new immune target for anti-TAM treatment in a subset of NSCLC patients, possibly in combination with available immune checkpoint inhibitors.
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| 2. |
- Backman, Max, et al.
(author)
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Extending the immune phenotypes of lung cancer: Oasis in the desert
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Other publication (other academic/artistic)abstract
- Introduction: Tumor infiltrating immune cells are key elements of the tumor microenvironment and mediate the anti-tumor effects of immunotherapy. The aim of the study was to characterize patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to tumor mutations and clinicopathological parameters. Methods: Lymphocytes (CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+) and PD-L1+ were annotated on a tissue microarray including 357 operated NSCLC cases. Somatic mutations and tumor mutational burden were analyzed by targeted sequencing for 82 genes, and transcriptomic immune patterns were established in 197 patients based on RNAseq data. Results: We identified somatic mutations (TP53, NF1, KEAP1, CSMD3, LRP1B) that correlated with specific immune cell infiltrates. Hierarchical clustering revealed four immune classes: with (1) high immune cell infiltration (“inflamed”), (2) low immune cell infiltration (“desert”), (3) a mixed phenotype, and (4) a new phenotype with an overall muted inflammatory cell pattern but with an imprint of NK and plasma cells. This latter class exhibited low expression of immune response-related genes (e.g. CXCL9, GZMB, INFG, TGFB1), but was linked to better survival and therefore designated “oasis”. Otherwise, the four immune classes were not related to the presence of specific mutations (EGFR, KRAS, TP53) or histologic subtypes. Conclusion: We present a compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC and identified the novel immune class “oasis”. The immune classification helps to better define the immunogenic potency of NSCLC in the era of immunotherapy.
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| 3. |
- Backman, Max, et al.
(author)
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Infiltration of NK and plasma cells is associated with a distinct immune subset in non‐small cell lung cancer
- 2021
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In: Journal of Pathology. - : John Wiley & Sons. - 0022-3417 .- 1096-9896. ; 255:3, s. 243-256
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Journal article (peer-reviewed)abstract
- Immune cells of the tumor microenvironment are central but erratic targets for immunotherapy. The aim of this study was to characterize novel patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to its molecular and clinicopathologic characteristics. Lymphocytes (CD3+, CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+), PD1+, and PD-L1+ were annotated on a tissue microarray including 357 NSCLC cases. Somatic mutations were analyzed by targeted sequencing for 82 genes and a tumor mutational load score was estimated. Transcriptomic immune patterns were established in 197 patients based on RNA sequencing data. The immune cell infiltration was variable and showed only poor association with specific mutations. The previously defined immune phenotypic patterns, desert, inflamed, and immune excluded, comprised 30, 13, and 57% of cases, respectively. Notably, mRNA immune activation and high estimated tumor mutational load were unique only for the inflamed pattern. However, in the unsupervised cluster analysis, including all immune cell markers, these conceptual patterns were only weakly reproduced. Instead, four immune classes were identified: (1) high immune cell infiltration, (2) high immune cell infiltration with abundance of CD20+ B cells, (3) low immune cell infiltration, and (4) a phenotype with an imprint of plasma cells and NK cells. This latter class was linked to better survival despite exhibiting low expression of immune response-related genes (e.g. CXCL9, GZMB, INFG, CTLA4). This compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC reveals two previously unrecognized immune classes. A refined immune classification, including traits of the humoral and innate immune response, is important to define the immunogenic potency of NSCLC in the era of immunotherapy. © 2021 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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| 4. |
- Backman, Max, 1987-, et al.
(author)
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Spatial immunophenotyping of the tumor microenvironment in non-small cell lung cancer
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Other publication (other academic/artistic)abstract
- Introduction: Immune cells in the tumor microenvironment are associated with prognosis and response to therapy. We aimed to comprehensively characterize the spatial immune phenotypes in the mutational and clinicopathological background of non-small cell lung cancer (NSCLC).Methods: We established a multiplexed fluorescence multispectral imaging pipeline to spatially quantify 13 immune cell subsets in 359 NSCLC cases: CD4 effector cells (CD4 Eff), CD4 regulatory cells (CD4 Treg), CD8 effector cells (CD8 Eff), CD8 regulatory cells (CD8 Treg), B-cells, NK-cells, NKT-cells, M1 macrophages (M1), CD163+ myeloid cells (CD163), M2 macrophages (M2), immature dendritic cells (iDCs), mature dendritic cells (mDCs), and plasmacytoid dendritic cells (pDCs). Results: CD4 Eff cells, CD8 Eff cells, and M1 macrophages were the most abundant immune cells invading the tumor cell compartment and indicated a patient group with a favorable prognosis in the cluster analysis. Likewise, single densities of lymphocytic subsets (CD4 Eff, CD4 Treg, CD8 Treg, and B-cells), as well as pDCs, were independently associated with longer survival. However, when these immune cells were located close to CD8 Treg cells, the favorable impact was attenuated. In the multivariate Cox regression model including cell densities and distances, the densities of M1 and CD163 cells and distances between cells (CD8 Treg–B-cells, CD8 Eff–cancer cells, and B-cells–CD4 Treg) demonstrated positive prognostic impact, while short M2–M1 distances were prognostically unfavorable.Conclusion: We present a unique spatial profile of the in situ immune cell landscape in NSCLC as a publicly available data set. Cell densities and cell distances contribute independently to prognostic information on clinical outcomes, suggesting that spatial information is also crucial for diagnostic use.
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| 5. |
- Backman, Max, 1987-, et al.
(author)
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Spatial immunophenotyping of the tumour microenvironment in non-small cell lung cancer
- 2023
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In: European Journal of Cancer. - : Elsevier. - 0959-8049 .- 1879-0852. ; 185, s. 40-52
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Journal article (peer-reviewed)abstract
- Introduction: Immune cells in the tumour microenvironment are associated with prognosis and response to therapy. We aimed to comprehensively characterise the spatial im-mune phenotypes in the mutational and clinicopathological background of non-small cell lung cancer (NSCLC).Methods: We established a multiplexed fluorescence imaging pipeline to spatially quantify 13 immune cell subsets in 359 NSCLC cases: CD4 effector cells (CD4-Eff), CD4 regulatory cells (CD4-Treg), CD8 effector cells (CD8-Eff), CD8 regulatory cells (CD8-Treg), B-cells, natural killer cells, natural killer T-cells, M1 macrophages (M1), CD163 thorn myeloid cells (CD163), M2 macrophages (M2), immature dendritic cells (iDCs), mature dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs).Results: CD4-Eff cells, CD8-Eff cells and M1 macrophages were the most abundant immune cells invading the tumour cell compartment and indicated a patient group with a favourable prognosis in the cluster analysis. Likewise, single densities of lymphocytic subsets (CD4-Eff, CD4-Treg, CD8-Treg, B-cells and pDCs) were independently associated with longer survival. However, when these immune cells were located close to CD8-Treg cells, the favourable impact was attenuated. In the multivariable Cox regression model, including cell densities and distances, the densities of M1 and CD163 cells and distances between cells (CD8-Treg-B-cells, CD8-Eff-cancer cells and B-cells-CD4-Treg) demonstrated positive prognostic impact, whereas short M2-M1 distances were prognostically unfavourable.Conclusion: We present a unique spatial profile of the in situ immune cell landscape in NSCLC as a publicly available data set. Cell densities and cell distances contribute independently to prognostic information on clinical outcomes, suggesting that spatial information is crucial for diagnostic use.
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| 6. |
- Eltahir, Mohamed, et al.
(author)
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Plasma Proteomic Analysis in Non-Small Cell Lung Cancer Patients Treated with PD-1/PD-L1 Blockade
- 2021
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In: Cancers. - : MDPI. - 2072-6694. ; 13:13
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Journal article (peer-reviewed)abstract
- Simple Summary Immunotherapy leads to highly variable responses in lung cancer patients. We assessed the value of a blood-based test to predict which patients would benefit from this new treatment modality. We determined that some patients have higher and lower levels of immune markers in their blood samples, and that this is related to better survival without tumor growth. The blood test has the potential to help select the optimal therapy for lung cancer patients. Checkpoint inhibitors have been approved for the treatment of non-small cell lung cancer (NSCLC). However, only a minority of patients demonstrate a durable clinical response. PD-L1 scoring is currently the only biomarker measure routinely used to select patients for immunotherapy, but its predictive accuracy is modest. The aim of our study was to evaluate a proteomic assay for the analysis of patient plasma in the context of immunotherapy. Pretreatment plasma samples from 43 NSCLC patients who received anti-PD-(L)1 therapy were analyzed using a proximity extension assay (PEA) to quantify 92 different immune oncology-related proteins. The plasma protein levels were associated with clinical and histopathological parameters, as well as therapy response and survival. Unsupervised hierarchical cluster analysis revealed two patient groups with distinct protein profiles associated with high and low immune protein levels, designated as "hot" and "cold". Further supervised cluster analysis based on T-cell activation markers showed that higher levels of T-cell activation markers were associated with longer progression-free survival (PFS) (p < 0.01). The analysis of single proteins revealed that high plasma levels of CXCL9 and CXCL10 and low ADA levels were associated with better response and prolonged PFS (p < 0.05). Moreover, in an explorative response prediction model, the combination of protein markers (CXCL9, CXCL10, IL-15, CASP8, and ADA) resulted in higher accuracy in predicting response than tumor PD-L1 expression or each protein assayed individually. Our findings demonstrate a proof of concept for the use of multiplex plasma protein levels as a tool for anti-PD-(L)1 response prediction in NSCLC. Additionally, we identified protein signatures that could predict the response to anti-PD-(L)1 therapy.
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| 7. |
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| 8. |
- Isaksson-Daun, Johan, et al.
(author)
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Using Portable Virtual Reality to Assess Mobility of Blind and Low-Vision Individuals With the Audomni Sensory Supplementation Feedback
- 2024
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In: IEEE Access. - 2169-3536. ; 12
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Journal article (peer-reviewed)abstract
- Numerous electronic travel aids (ETAs) to increase the mobility of blind or low-vision (BLV) individuals have been proposed. However, the lack of established and well-motivated methods, and of recruiting enough BLV test participants, keeps a successful aid illusory. To combat this, a new aid-agnostic questionnaire focused on mobility, the Desire of Use Questionnaire for Mobility of BLV individuals (DoUQ-MoB) and a new portable, large-scale-exploration virtual reality (VR) system, the Parrot-VR, were employed to evaluate the ETA Audomni. Through VR and Audomni, 19 heterogenous BLV participants traversed large-scale urban environments. Their experiences were probed through the DoUQ-MoB, and their movement analyzed. Numerous results are presented, a highlight being that most participants, 76 %, responded that it was very or extremely likely that they would want to use Audomni along with their current aid. Further, Parrot-VR assists in recruiting a satisfying number of diverse BLV participants; and DoUQ-MoB allows to systematically probe their opinions of an aid, and how it relates to others aids, in a considerable quantity of mobility aid aspects. This work illuminates some shortcomings of Audomni, but also shows a majority of BLV participants actually wanting to use a proposed ETA — a result rarely seen so distinctly in the field, and which encourages the continuing efforts of the project. The results are supported by a novel test procedure, which might serve as future inspiration to the field.
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| 9. |
- Isaksson, Johan, et al.
(author)
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Audomni : Super-Scale Sensory Supplementation to Increase the Mobility of Blind and Low-Vision Individuals - A Pilot Study
- 2020
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In: IEEE Transactions on Neural Systems and Rehabilitation Engineering. - 1534-4320. ; 28:5, s. 1187-1197
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Journal article (peer-reviewed)abstract
- Objective: Blindness and low vision have severe effects on individuals' quality of life and socioeconomic cost; a main contributor of which is a prevalent and acutely decreased mobility level. To alleviate this, numerous technological solutions have been proposed in the last 70 years; however, none has become widespread. Method: In this paper, we introduce the vision-to-audio, super-scale sensory substitution/supplementation device Audomni; we address the field-encompassing issues of ill-motivated and overabundant test methodologies and metrics; and we utilize our proposed Desire of Use model to evaluate proposed pilot user tests, their results, and Audomni itself. Results: Audomni holds a spatial resolution of 80 x 60 pixels at 1.2° angular resolution and close to real-time temporal resolution, outdoor-viable technology, and several novel differentiation methods. The tests indicated that Audomni has a low learning curve, and several key mobility subtasks were accomplished; however, the tests would benefit from higher real-life motivation and data collection affordability. Conclusion: Audomni shows promise to be a viable mobility device - with some addressable issues. Employing Desire of Use to design future tests should provide both high real-life motivation and relevance to them. Significance: As far as we know, Audomni features the greatest information conveyance rate in the field, yet seems to offer comprehensible and fairly intuitive sonification; this work is also the first to utilize Desire of Use as a tool to evaluate user tests, a device, and to lay out an overarching project aim.
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| 10. |
- Isaksson, Johan, et al.
(author)
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Community Violence Exposure and Eating Disorder Symptoms among Belgian, Russian and US Adolescents : Cross-Country and Gender Perspectives.
- 2023
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In: Child Psychiatry and Human Development. - : Springer. - 0009-398X .- 1573-3327.
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Journal article (peer-reviewed)abstract
- Community violence exposure (CVE) is one of the most common adverse childhood experiences worldwide. Despite this, its potential effect on disordered eating in adolescents from different cultures is underexplored. In the present cross-sectional study, self-reported data were collected from 9751 students (Mean age = 14.27) from Belgium, Russia and the US on CVE (witnessing violence and violence victimization), eating disorder (ED) symptoms (ED thoughts with associated compensatory behaviors), and comorbid symptoms of posttraumatic stress, depression and anxiety. Increased CVE (from no exposure to witnessing to victimization) was associated with more ED symptoms, and the associations remained significant after adjusting for comorbid conditions. The associations were similar for adolescents across the three countries. No gender differences were observed in the association between CVE and ED symptoms, even though girls in general reported more ED symptoms than boys. We conclude that CVE appears to be associated with ED symptoms in three culturally different samples of adolescents.
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