uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Alternative names
Publications (10 of 86) Show all publications
Dietel, M., Savelov, N., Salanova, R., Micke, P., Bigras, G., Hida, T., . . . Deitz, A. (2018). 30O Real-world prevalence of PD-L1 expression in locally advanced or metastatic non-small cell lung cancer (NSCLC): The global, multicentre EXPRESS study. Paper presented at European Lung Cancer Congress (ELCC), 11-14 April 2018, Geneva, Switzerland.. Journal of Thoracic Oncology, 13(4), S74-S75
Open this publication in new window or tab >>30O Real-world prevalence of PD-L1 expression in locally advanced or metastatic non-small cell lung cancer (NSCLC): The global, multicentre EXPRESS study
Show others...
2018 (English)In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 13, no 4, p. S74-S75Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
New York: Elsevier, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-368922 (URN)10.1016/S1556-0864(18)30404-0 (DOI)000436557600125 ()
Conference
European Lung Cancer Congress (ELCC), 11-14 April 2018, Geneva, Switzerland.
Note

Meeting Abstract: 130O

WoS title: Real-world prevalence of PD-L1 expression in locally advanced or metastatic non-small cell lung cancer (NSCLC): The global, multicentre EXPRESS study

Available from: 2018-12-11 Created: 2018-12-11 Last updated: 2018-12-11Bibliographically approved
Miyashita, N., Horie, M., Suzuki, H. I., Yoshihara, M., Djureinovic, D., Persson, J., . . . Nagase, T. (2018). An Integrative Analysis of Transcriptome and Epigenome Features of ASCL1-Positive Lung Adenocarcinomas. Journal of Thoracic Oncology, 13(11), 1676-1691
Open this publication in new window or tab >>An Integrative Analysis of Transcriptome and Epigenome Features of ASCL1-Positive Lung Adenocarcinomas
Show others...
2018 (English)In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 13, no 11, p. 1676-1691Article in journal (Refereed) Published
Abstract [en]

Introduction: A subgroup of lung adenocarcinoma shows neuroendocrine differentiation and expression of achaete-scute family bHLH transcription factor 1 (ASCL1), common to high-grade neuroendocrine tumors, small-cell lung cancer and large cell neuroendocrine carcinoma. Methods: The aim of this study was to characterize clinical and molecular features of ASCL1-positive lung adenocarcinoma by using recent transcriptome profiling in multiple patient cohorts and genome-wide epigenetic profiling including data from The Cancer Genome Atlas. Results: The ASCL1-positive subtype of lung adenocarcinoma developed preferentially in current or former smokers and usually did not harbor EGFR mutations. In transcriptome profiling, this subtype overlapped with the recently proposed proximal-proliferative molecular subtype. Gene expression profiling of ASCL1-positive cases suggested generally poor immune cell infiltration and none of the tumors were positive for programmed cell death ligand 1 protein expression. Genome-wide methylation analysis showed global DNA hypomethylation in ASCL1-positive cases. ASCL1 was associated with super-enhancers in ASCL1-positive lung adenocarcinoma cells, and ASCL1 silencing suppressed other super-enhancer-associated genes, suggesting thatASCL1 acts as a master transcriptional regulator. This was further reinforced by the essential roles of ASCL1 in cell proliferation, survival, and cell cycle control. Conclusions: These results suggest that ASCL1 defines a subgroup of lung adenocarcinoma with distinct molecular features by driving super-enhancer-mediated transcriptional programs.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC, 2018
Keywords
Lung cancer, Adenocarcinoma, Neuroendocrine, ASCL1, NSCLC
National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-371088 (URN)10.1016/j.jtho.2018.07.096 (DOI)000450088600020 ()30121393 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Cancer Society
Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2019-01-07Bibliographically approved
Horie, M., Miyashita, N., Mattsson, J. S., Mikami, Y., Sandelin, M., Brunnstrom, H., . . . Saito, A. (2018). An integrative transcriptome analysis reveals a functional role for thyroid transcription factor-1 in small cell lung cancer. Journal of Pathology, 246(2), 154-165
Open this publication in new window or tab >>An integrative transcriptome analysis reveals a functional role for thyroid transcription factor-1 in small cell lung cancer
Show others...
2018 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 246, no 2, p. 154-165Article in journal (Refereed) Published
Abstract [en]

Small cell lung cancer (SCLC) is a neuroendocrine tumour that exhibits rapid growth and metastatic spread. Although SCLC represents a prototypically undifferentiated cancer type, thyroid transcription factor-1 (TTF-1, gene symbol NKX2-1), a master regulator for pulmonary epithelial cell differentiation and lung morphogenesis, is strongly upregulated in this aggressive cancer type. The aim of this study was to evaluate a functional role for TTF-1 in SCLC. We demonstrated that achaete-scute complex homolog 1 (ASCL1), an essential transcription factor for neuroendocrine differentiation, positively regulated TTF-1 in SCLC cell lines. Subsequently, we described genes and microRNAs (miRNAs) that were possibly controlled by TTF-1 and identified nuclear factor IB (NFIB), a recently characterised driver of SCLC progression, as a transcriptional target of TTF-1. Our findings shine light on a regulatory axis in SCLC consisting of ASCL1/TTF-1/NFIB that potentially contributes to the tumourigenesis of SCLC.

Keywords
SCLC, ASCL1, TTF-1, NFIB, neuroendocrine differentiation
National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-366945 (URN)10.1002/path.5109 (DOI)000445203500004 ()29876935 (PubMedID)
Available from: 2018-11-28 Created: 2018-11-28 Last updated: 2019-01-04Bibliographically approved
Gulyas, M., Mattsson, J. S., Lindgren, A., Ek, L., Lamberg Lundström, K., Behndig, A., . . . Bergman, B. (2018). COX-2 expression and effects of celecoxib in addition to standard chemotherapy in advanced non-small cell lung cancer.. Acta Oncologica, 57(2), 244-250
Open this publication in new window or tab >>COX-2 expression and effects of celecoxib in addition to standard chemotherapy in advanced non-small cell lung cancer.
Show others...
2018 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 2, p. 244-250Article in journal (Refereed) Published
Abstract [en]

Aim: Inhibition of cyclooxygenase-2 (COX-2) is proposed as a treatment option in several cancer types. However, in non-small cell lung cancer (NSCLC), phase III trials have failed to demonstrate a benefit of adding COX-2 inhibitors to standard chemotherapy. The aim of this study was to analyze COX-2 expression in tumor and stromal cells as predictive biomarker for COX-2 inhibition.

Methods: In a multicenter phase III trial, 316 patients with advanced NSCLC were randomized to receive celecoxib (400 mg b.i.d.) or placebo up to one year in addition to a two-drug platinum-based chemotherapy combination. In a subset of 122 patients, archived tumor tissue was available for immunohistochemical analysis of COX-2 expression in tumor and stromal cells. For each compartment, COX-2 expression was graded as high or low, based on a product score of extension and intensity of positively stained cells.

Results: An updated analysis of all 316 patients included in the original trial, and of the 122 patients with available tumor tissue, showed no survival differences between the celecoxib and placebo arms (HR 1.01; 95% CI 0.81–1.27 and HR 1.12; 95% CI 0.78–1.61, respectively). High COX-2 scores in tumor (n = 71) or stromal cells (n = 55) was not associated with a superior survival outcome with celecoxib vs. placebo (HR =0.96, 95% CI 0.60–1.54; and HR =1.51; 95% CI 0.86–2.66), and no significant interaction effect between COX-2 score in tumor or stromal cells and celecoxib effect on survival was detected (p = .48 and .25, respectively).

Conclusions: In this subgroup analysis of patients with advanced NSCLC treated within the context of a randomized trial, we could not detect any interaction effect of COX-2 expression in tumor or stromal cells and the outcome of celecoxib treatment in addition to standard chemotherapy.

National Category
Clinical Medicine Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-343645 (URN)10.1080/0284186X.2017.1400685 (DOI)000423473200011 ()29140138 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2018-03-09Bibliographically approved
Djureinovic, D., Dodig-Crnkovic, T., Hellström, C., Holgersson, G., Bergqvist, M., Mattsson, J., . . . Micke, P. (2018). Detection of autoantibodies against cancer-testis antigens in non-small cell lung cancer. Lung Cancer, 125, 157-163
Open this publication in new window or tab >>Detection of autoantibodies against cancer-testis antigens in non-small cell lung cancer
Show others...
2018 (English)In: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 125, p. 157-163Article in journal (Refereed) Published
Abstract [en]

Cancer testis antigens (CTAs) are defined as proteins that are specifically expressed in testis or placenta and their expression is frequently activated in cancer. Due to their ability to induce an immune response, CTAs may serve as suitable targets for immunotherapy. The aim of this study was to evaluate if there is reactivity against CTAs in the plasma of non-small cell lung cancer (NSCLC) patients through the detection of circulating antibodies. 

To comprehensively analyse auto-antibodies against CTAs the multiplexing capacities of suspension bead array technology was used. Bead arrays were created with 120 protein fragments, representing 112 CTAs. Reactivity profiles were measured in plasma samples from 133 NSCLC patients and 57 cases with benign lung diseases. Altogether reactivity against 69 antigens, representing 81 CTAs, was demonstrated in at least one of the analysed samples. Twenty-nine of the antigens (45 CTAs) demonstrated exclusive reactivity in NSCLC samples. Reactivity against CT47A genes, PAGE3, VCX, MAGEB1, LIN28B and C12orf54 were only found in NSCLC patients at a frequency of 1%-4%. The presence of autoantibodies towards these six antigens was confirmed in an independent group of 34 NSCLC patients.

In conclusion, we identified autoantibodies against CTAs in the plasma of lung cancer patients. The reactivity pattern of autoantibodies was higher in cancer patients compared to the benign group, stable over time, but low in frequency of occurrence. The findings suggest that some CTAs are immunogenic and that these properties can be utilized as immune targets.

Keywords
Lung cancer, adenocarcinoma, squamous cell cancer, cancer immunity, tumor markers, MAGE, PAGE
National Category
Medical and Health Sciences Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-347809 (URN)10.1016/j.lungcan.2018.09.012 (DOI)000450378500023 ()
Funder
Swedish Cancer Society, 2012/738Knut and Alice Wallenberg FoundationErik, Karin och Gösta Selanders Foundation
Available from: 2018-04-07 Created: 2018-04-07 Last updated: 2019-01-04Bibliographically approved
Micke, P., Björk, L., Backman, M., Elfving, H., Mattsson, J., Mezheyeuski, A., . . . Burlutskiy, N. (2018). Digital pathology 2.0: a deep learning image analysis tool to identify lung cancer in human tissue samples. Virchows Archiv, 473, S106-S107
Open this publication in new window or tab >>Digital pathology 2.0: a deep learning image analysis tool to identify lung cancer in human tissue samples
Show others...
2018 (English)In: Virchows Archiv, ISSN 0945-6317, E-ISSN 1432-2307, Vol. 473, p. S106-S107Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Springer, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-367145 (URN)000443414101401 ()
Available from: 2018-11-29 Created: 2018-11-29 Last updated: 2018-11-29Bibliographically approved
La Fleur, L., Boura, V. F., Alexeyenko, A., Berglund, A., Ponten, V., Mattsson, J. S., . . . Botling, J. (2018). Expression of scavenger receptor MARCO defines a targetable tumor-associated macrophage subset in non-small cell lung cancer. International Journal of Cancer, 143(7), 1741-1752
Open this publication in new window or tab >>Expression of scavenger receptor MARCO defines a targetable tumor-associated macrophage subset in non-small cell lung cancer
Show others...
2018 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 143, no 7, p. 1741-1752Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
WILEY, 2018
Keywords
lung cancer, MARCO, tumor-associated macrophages, immune therapy, PD-L1
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-364230 (URN)10.1002/ijc.31545 (DOI)000443392100020 ()29667169 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2018-10-24 Created: 2018-10-24 Last updated: 2018-10-24Bibliographically approved
Karlsson, T., Kvarnbrink, S., Holmlund, C., Botling, J., Micke, P., Henriksson, R., . . . Hedman, H. (2018). LMO7 and LIMCH1 interact with LRIG proteins in lung cancer, with prognostic implications for early-stage disease. Lung Cancer, 125, 174-184
Open this publication in new window or tab >>LMO7 and LIMCH1 interact with LRIG proteins in lung cancer, with prognostic implications for early-stage disease
Show others...
2018 (English)In: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 125, p. 174-184Article in journal (Refereed) Published
Abstract [en]

Objectives: The human leucine-rich repeats and immunoglobulin-like domains (LRIG) protein family comprises the integral membrane proteins LRIG1, LRIG2 and LRIG3. LRIG1 is frequently down-regulated in human cancer, and high levels of LRIG1 in tumor tissue are associated with favorable clinical outcomes in several tumor types including non-small cell lung cancer (NSCLC). Mechanistically, LRIG1 negatively regulates receptor tyrosine kinases and functions as a tumor suppressor. However, the details of the molecular mechanisms involved are poorly understood, and even less is known about the functions of LRIG2 and LRIG3. The aim of this study was to further elucidate the functions and molecular interactions of the LRIG proteins.

Materials and methods: A yeast two-hybrid screen was performed using a cytosolic LRIG3 peptide as bait. In transfected human cells, co-immunoprecipitation and co-localization experiments were performed. Proximity ligation assay was performed to investigate interactions between endogenously expressed proteins. Expression levels of LMO7 and LIMCH1 in normal and malignant lung tissue were investigated using qRT-PCR and through in silico analyses of public data sets. Finally, a clinical cohort comprising 355 surgically treated NSCLC cases was immunostained for LMO7.

Results: In the yeast two-hybrid screen, the two paralogous proteins LMO7 and LIMCH1 were identified as interaction partners to LRIG3. LMO7 and LIMCH1 co-localized and co-immunoprecipitated with both LRIG1 and LRIG3. Endogenously expressed LMO7 was in close proximity of both LRIG1 and LRIG3. LMO7 and LIMCH1 were highly expressed in normal lung tissue and down-regulated in malignant lung tissue. LMO7 immunoreactivity was shown to be a negative prognostic factor in LRIG1 positive tumors, predicting poor patient survival.

Conclusion: These findings suggest that LMO7 and LIMCH1 physically interact with LRIG proteins and that expression of LMO7 is of clinical importance in NSCLC.

Keywords
Non-small cell lung cancer, Lung cancer, Prognosis, LRIG1, LRIG3, LMO7, LIMCH1
National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-371554 (URN)10.1016/j.lungcan.2018.09.017 (DOI)000450378500025 ()30429017 (PubMedID)
Funder
The Kempe FoundationsSwedish Cancer Society
Available from: 2018-12-21 Created: 2018-12-21 Last updated: 2019-01-04Bibliographically approved
Mezheyeuski, A., Bergsland, C. H., Backman, M., Djureinovic, D., Sjöblom, T., Bruun, J. & Micke, P. (2018). Multispectral imaging for quantitative and compartment-specific immune infiltrates reveals distinct immune profiles that classify lung cancer patients.. Journal of Pathology, 244(4), 421-431
Open this publication in new window or tab >>Multispectral imaging for quantitative and compartment-specific immune infiltrates reveals distinct immune profiles that classify lung cancer patients.
Show others...
2018 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 244, no 4, p. 421-431Article in journal (Refereed) Published
Abstract [en]

Semiquantitative assessment of immune markers by immunohistochemistry (IHC) has significant limitations for describing the diversity of the immune response in cancer. Therefore, we evaluated a fluorescence-based multiplexed immunohistochemical method in combination with a multispectral imaging system to quantify immune infiltrates in situ in the environment of non-small-cell lung cancer (NSCLC). A tissue microarray including 57 NSCLC cases was stained with antibodies against CD8, CD20, CD4, FOXP3, CD45RO, and pan-cytokeratin, and immune cells were quantified in epithelial and stromal compartments. The results were compared with those of conventional IHC, and related to corresponding RNA-sequencing (RNAseq) expression values. We found a strong correlation between the visual and digital quantification of lymphocytes for CD45RO (correlation coefficient: r = 0.52), FOXP3 (r = 0.87), CD4 (r = 0.79), CD20 (r = 0.81) and CD8 (r = 0.90) cells. The correlation with RNAseq data for digital quantification (0.35-0.65) was comparable to or better than that for visual quantification (0.38-0.58). Combination of the signals of the five immune markers enabled further subpopulations of lymphocytes to be identified and localized. The specific pattern of immune cell infiltration based either on the spatial distribution (distance between regulatory CD8(+) T and cancer cells) or the relationships of lymphocyte subclasses with each other (e.g. cytotoxic/regulatory cell ratio) were associated with patient prognosis. In conclusion, the fluorescence multiplexed immunohistochemical method, based on only one tissue section, provided reliable quantification and localization of immune cells in cancer tissue. The application of this technique to clinical biopsies can provide a basic characterization of immune infiltrates to guide clinical decisions in the era of immunotherapy.

Keywords
PD-L1, checkpoint therapy, deep-learning microscopy, digital pathology, prognosis, tumour microenvironment
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-343644 (URN)10.1002/path.5026 (DOI)000428213800006 ()29282718 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2018-06-20Bibliographically approved
Westerlund, K., Altai, M., Mitran, B., Konijnenberg, M., Oroujeni, M., Atterby, C., . . . Tolmachev, V. (2018). Radionuclide Therapy of HER2-Expressing Human Xenografts Using Affibody-Based Peptide Nucleic Acid-Mediated Pretargeting: In Vivo Proof of Principle. Journal of Nuclear Medicine, 59(7), 1092-1098
Open this publication in new window or tab >>Radionuclide Therapy of HER2-Expressing Human Xenografts Using Affibody-Based Peptide Nucleic Acid-Mediated Pretargeting: In Vivo Proof of Principle
Show others...
2018 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 59, no 7, p. 1092-1098Article in journal (Refereed) Published
Abstract [en]

Affibody molecules are small proteins engineered using a nonanti-body scaffold. Radiolabeled Affibody molecules are excellent imaging probes, but their application to radionuclide therapy has been prevented by high renal reabsorption. The aim of this study was to test the hypothesis that Affibody-based peptide nucleic acid (PNA)-mediated pretargeted therapy of human epidermal growth factor receptor 2 (HER2)-expressing cancer extends survival without accompanying renal toxicity.

Methods: A HER2-targeting Affibody molecule ligated with an AGTCGTGATGTAGTC PNA hybridization probe (Z(HER2:342)-SR-HP1) was used as the primary pretargeting agent. A complementary AGTCGTGATGTAGTC PNA conjugated to the chelator DOTA and labeled with the radionuclide Lu-177 (Lu-177-HP2) was used as the secondary agent. The influence of different factors on pretargeting was investigated. Experimental radionuclide therapy in mice bearing SKOV-3 xenografts was performed in 6 cycles separated by 7 d.

Results: Optimal tumor targeting was achieved when 16 MBq/3.5 mu g (0.65 nmol) of Lu-177-HP2 was injected 16 h after injection of 100 mu g (7.7 nmol) of Z(HER2:342)-SR-HP1. The calculated absorbed dose to tumors was 1,075 mGy/MBq, whereas the absorbed dose to kidneys was 206 mGy/MBq and the absorbed dose to blood (surrogate of bone marrow) was 4 mGy/MBq. Survival of mice was significantly longer (P < 0.05) in the treatment group (66 d) than in the control groups treated with the same amount of Z(HER2:342)-SR-HP1 only (37 d), the same amount and activity of Lu-177-HP2 only (32 d), or phosphate-buffered saline (37 d).

Conclusion: The studied pretargeting system can deliver an absorbed dose to tumors appreciably exceeding absorbed doses to critical organs, making Affibody-based PNA-mediated pretargeted radionuclide therapy highly attractive.

Keywords
pretargeting, PNA, affibody molecules, radionuclide therapy, HER2
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-358030 (URN)10.2967/jnumed.118.208348 (DOI)000437237200028 ()29439013 (PubMedID)
Funder
Swedish Cancer SocietyVINNOVASwedish Research Council
Note

Kristina Westerlund and Mohamed Altai contributed equally. Amelie Eriksson Karlström and Vladimir Tolmachev contributed equally.

Available from: 2018-08-23 Created: 2018-08-23 Last updated: 2018-09-18Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-1210-5961

Search in DiVA

Show all publications