| 1. |
- Backman, Max, et al.
(författare)
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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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Ingår i: Journal of Pathology. - : John Wiley & Sons. - 0022-3417 .- 1096-9896. ; 255:3, s. 243-256
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Tidskriftsartikel (refereegranskat)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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| 2. |
- Backman, Max, 1987-, et al.
(författare)
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Spatial immunophenotyping of the tumor microenvironment in non-small cell lung cancer
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Annan publikation (övrigt vetenskapligt/konstnärligt)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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| 3. |
- Backman, Max, 1987-, et al.
(författare)
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Spatial immunophenotyping of the tumour microenvironment in non-small cell lung cancer
- 2023
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Ingår i: European Journal of Cancer. - : Elsevier. - 0959-8049 .- 1879-0852. ; 185, s. 40-52
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Tidskriftsartikel (refereegranskat)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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| 4. |
- Johannesson, Petra, et al.
(författare)
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SAR and optimization of trioxoisothiazole-based liver receptor X (LXR) agonists leading to the clinical candidate AZD3971
- 2014
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Ingår i: Division of Medicinal Chemistry. ; , s. 247-247
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Konferensbidrag (refereegranskat)abstract
- The liver X receptors (LXRα and LXRβ) are members of the nuclear receptor family of transcription factors. The activation of LXR induces genes involved in reverse cholesterol transport (RCT), which is believed to be the main effect of LXR agonists in the prevention or treatment of atherosclerosis. However LXR agonists have also been shown to cause hepatic steatosis and hypertriglyceridaemia. The ability to separate beneficial effects from negative effects has been a challenge that so far has hampered the development of LXR agonists for human use. We herein describe the SAR and optimization of a series of trioxoisothiazole-based LXR agonists leading to compounds with nanomolar potencies and a separation of beneficial versus negative effects in vivo. This work ultimately led to the nomination of AZD3971 as a candidate for the treatment of atherosclerosis.
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