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  • 1.
    Aasebö, Kristine Ö.
    et al.
    Univ Bergen, Dept Clin Sci, Bergen, Norway.
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Sundström, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Mezheyeuski, Artur
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Edqvist, Per-Henrik D
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Eide, Geir Egil
    Univ Bergen, Dept Global Publ Hlth & Primary Care, Lifestyle Epidemiol Grp, Bergen, Norway;Haukeland Hosp, Ctr Clin Res, Bergen, Norway.
    Pontén, Fredrik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Pfeiffer, Per
    Odense Univ Hosp, Dept Oncol, Odense, Denmark.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Sorbye, Halfdan
    Univ Bergen, Dept Clin Sci, Bergen, Norway;Haukeland Hosp, Dept Oncol, Bergen, Norway.
    Consequences of a high incidence of microsatellite instability and BRAF-mutated tumors: A population-based cohort of metastatic colorectal cancer patients2019Ingår i: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 8, nr 7, s. 3623-3635Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Immunotherapy for patients with microsatellite-instable (MSI-H) tumors or BRAF-inhibitors combination treatment for BRAF-mutated (mutBRAF) tumors in metastatic colorectal cancer (mCRC) is promising, but the frequency of these molecular changes in trial patients are low. Unselected population-based studies of these molecular changes are warranted.

    Methods: A population-based cohort of 798 mCRC patients in Scandinavia was studied. Patient and molecular tumor characteristics, overall survival (OS) and progression-free survival (PFS) were estimated.

    Results: Here, 40/583 (7%) tumor samples were MSI-H and 120/591 (20%) were mutBRAF; 87% of MSI-H tumors were mutBRAF (non-Lynch). Elderly (>75 years) had more often MSI-H (10% vs 6%) and MSI-H/mutBRAF (9% vs 4%) tumors. Response rate (5% vs 44%), PFS (4 vs 8 months), and OS (9 vs 18 months) after first-line chemotherapy was all significantly lower in patients with MSI-H compared to patients with microsatellite stable tumors. MSI-H and mutBRAF were both independent poor prognostic predictors for OS (P = 0.049, P < 0.001) and PFS (P = 0.045, P = 0.005) after first-line chemotherapy. Patients with MSI-H tumors received less second-line chemotherapy (15% vs 37%, P = 0.005).

    Conclusions: In unselected mCRC patients, MSI-H and mutBRAF cases were more common than previously reported. Patients with MSI-H tumors had worse survival, less benefit from chemotherapy, and they differed considerably from recent third-line immunotherapy trial patients as they were older and most had mutBRAF tumor (non-Lynch).

  • 2.
    Backman, Max
    et al.
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    La Fleur, Linnea
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Kurppa, Pinja
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Djureinovic, Dijana
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Elfving, Hedvig
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Brunnström, Hans
    Division of Pathology, Lund University, Skåne University Hospital, Lund, Sweden.
    Mattsson, Johanna Sofia Margareta
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Pontén, Victor
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Eltahir, Mohamed
    Department of Pharmaceutical Bioscience, Uppsala University, Uppsala, Sweden.
    Mangsbo, Sara
    Department of Pharmaceutical Bioscience, Uppsala University, Uppsala, Sweden.
    Isaksson, Johan
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; Dept. of Respiratory Medicine, Gävle Hospital, Gävle, Sweden..
    Jirström, Karin
    Division of Pathology, Lund University, Skåne University Hospital, Lund, Sweden.
    Kärre, Klas
    Department of Microbiology, Cell and Tumor Biology (MTC), Karolinska Institutet, Stockholm, Sweden..
    Carbone, Ennio
    Department of Microbiology, Cell and Tumor Biology (MTC), Karolinska Institutet, Stockholm, Sweden; Tumor Immunology and Immunopathology Laboratory, Dept. of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, Catanzaro, Italy..
    Leandersson, Karin
    Cancer Immunology, Dept. of Translational Medicine, Lund University, Skånes University Hospital, Malmö, Sweden.
    Mezheyeuski, Artur
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Pontén, Fredrik
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Lindskog, Cecilia
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Botling, Johan
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Micke, Patrick
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Extending the immune phenotypes of lung cancer: Oasis in the desertManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    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. 

  • 3.
    Corvigno, Sara
    et al.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Frodin, Magnus
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Wisman, G. Bea A.
    Univ Groningen, Univ Med Ctr Groningen, Dept Gynecol Oncol, Groningen, Netherlands..
    Nijman, Hans W.
    Univ Groningen, Univ Med Ctr Groningen, Dept Gynecol Oncol, Groningen, Netherlands..
    Van der Zee, Ate G. J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Gynecol Oncol, Groningen, Netherlands..
    Jirstrom, Karin
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden..
    Nodin, Bjorn
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden..
    Hrynchyk, Ina
    City Clin Pathologoanat Bur, Minsk, Byelarus..
    Edler, David
    Karolinska Univ Hosp Solna, Dept Mol Med & Surg, Stockholm, Sweden..
    Ragnhammar, Peter
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Johansson, Martin
    Skanes Univ Sjukhus, Dept Lab Med, Malmo, Sweden..
    Dahlstrand, Hanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Mezheyeuski, Artur
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Ostman, Arne
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Multi-parametric profiling of renal cell, colorectal, and ovarian cancer identifies tumour-type-specific stroma phenotypes and a novel vascular biomarker2017Ingår i: The journal of pathology. Clinical research, ISSN 2056-4538, Vol. 3, nr 3, s. 214-224Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A novel set of integrated procedures for quantification of fibroblast-rich stroma and vascular characteristics has recently been presented allowing discovery of novel perivascular and stromal biomarkers in colorectal, renal cell, and ovarian cancer. In the present study, data obtained through these procedures from clinically well-annotated collections of these three tumour types have been used to address two novel questions. First, data have been used to investigate if the three tumour types demonstrate significant differences regarding features such as vessel diameter, vessel density, and perivascular marker expression. Second, analyses of the cohorts have been used to explore the prognostic significance of a novel vascular metric, 'vessel distance inter-quartile range (IQR)' that describes intra-case heterogeneity regarding vessel distribution. The comparisons between the three tumour types demonstrated a set of significant differences. Vessel density of renal cell cancer was statistically significantly higher than in colorectal and ovarian cancer. Vessel diameter was statistically significantly higher in ovarian cancer. Concerning perivascular status, colorectal cancer displayed significantly higher levels of perivascular PDGFR-beta expression than the other two tumour types. Intra-case heterogeneity of perivascular PDGFR-beta expression was also higher in colorectal cancer. Notably, these fibroblast-dominated stroma phenotypes matched previously described experimental tumour stroma characteristics, which have been linked to differential sensitivity to anti-VEGF drugs. High 'vessel distance IQR' was significantly associated with poor survival in both renal cell cancer and colorectal cancer. In renal cell cancer, this characteristic also acted as an independent prognostic marker according to multivariate analyses including standard clinico-pathological characteristics. Explorative subset analyses indicated particularly strong prognostic significance of 'vessel distance IQR' in T stage 4 of this cancer type. Together, these analyses identified tumour-type-specific vascular-stroma phenotypes of possible functional significance, and suggest 'vessel distance IQR' as a novel prognostic biomarker.

  • 4.
    Hammarström, Klara
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Mezheyeuski, Artur
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Korsavidou Hult, Nafsika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Sjöblom, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Stage distribution utilizing magnetic resonance imaging in an unselected population of primary rectal cancers2018Ingår i: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 44, nr 12, s. 1858-1864Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Pre-operative radiotherapy (RT) or chemo-radiotherapy (CRT) are sometimes recommended prior to rectal cancer surgery, but guideline recommendations vary. The aim was to describe stage distribution and other important characteristics required for the treatment decision of patients with primary rectal cancers utilizing magnetic resonance imaging (MRI) in an unselected population. Patients and methods: All 796 histopathologically verified rectal adenocarcinomas diagnosed 2010-2015 in two counties in Sweden (population 630,000 in 2015) were identified. Staging with pelvic MRI unless contraindications were present, treatment and pathology followed Swedish guidelines.

    Patients and methods: All 796 histopathologically verified rectal adenocarcinomas diagnosed 2010-2015 in two counties in Sweden (population 630,000 in 2015) were identified. Staging with pelvic MRI unless contraindications were present, treatment and pathology followed Swedish guidelines.

    Results: Twenty-three % of cases (n = 186) had distant metastases at diagnosis, demonstrating more advanced tumor and nodal stages when compared with non-metastatic patients (p < 0.001), and they more often displayed MRI-identified mucinous features and extramural vascular invasion (EMVI) than non-metastatic tumors (p < 0.001 for both). In non-metastatic patients, 8% displayed clinical stage T1 (cT1), 21% cT2, and 53% cT3; one-third of the latter threatened or involved the mesorectal fascia (MRF+). Almost 20% had stage cT4 (4% cT4a, 14% cT4b) of which 50% were considered "non-resectable". EMVI was seen in 33% of cT3M0 tumors and in 48% of cT4M0 tumors.

    Conclusions: In an unselected population, approximately 80% of primary rectal cancers are referred to as "locally advanced" (stage or cT3-4 or N+), meaning that they, according to many international guidelines, are recommended neo-adjuvant treatment. This study provides a detailed description of the clinical stages and presence of characteristics identifiable on MRI which are of importance when assessing the needs for RT/CRT, when using different guidelines. 

  • 5.
    Mezheyeuski, Artur
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Bergsland, Christian
    Oslo Univ Hosp, Oslo, Norway.
    Backman, Max
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Sjöblom, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Lothe, Ragnhild A.
    Oslo Univ Hosp, Oslo, Norway.
    Bruun, Jarle
    Oslo Univ Hosp, Oslo, Norway.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala Univ, Uppsala, Sweden.
    Digital multiplex immunofluorescence analysis identifies immune profiles in the tumor stroma associated with clinical outcome2018Ingår i: CANCER IMMUNOLOGY RESEARCH, ISSN 2326-6066, Vol. 6, nr 9 Suppl., artikel-id B30Artikel i tidskrift (Övrigt vetenskapligt)
  • 6.
    Mezheyeuski, Artur
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Bergsland, Christian Holst
    Backman, Max
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Djureinovic, Dijana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Sjöblom, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Bruun, Jarle
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Multispectral imaging for quantitative and compartment-specific immune infiltrates reveals distinct immune profiles that classify lung cancer patients.2018Ingår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 244, nr 4, s. 421-431Artikel i tidskrift (Refereegranskat)
    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.

  • 7.
    Mezheyeuski, Artur
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.
    Hrynchyk, Ina
    City Clin Pathologoanat Bur, Minsk, BELARUS.
    Herrera, Mercedes
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.
    Karlberg, Mia
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.
    Osterman, Eric
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Ragnhammar, Peter
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.
    Edler, David
    Karolinska Univ Hosp, Dept Mol Med & Surg, Stockholm, Sweden.
    Portyanko, Anna
    NN Alexandrov Natl Canc Ctr Belarus, Minsk, BELARUS.
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Sjöblom, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Ostman, Arne
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.
    Stroma-normalised vessel density predicts benefit from adjuvant fluorouracil-based chemotherapy in patients with stage II/III colon cancer2019Ingår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 121, nr 4, s. 303-311Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Identification of biomarkers associated with benefit of adjuvant chemotherapy in stage II/III colon cancer is an important task. METHODS: Vessel density (VD) and tumour stroma were analysed in a randomised-trial-derived discovery cohort (n = 312) and in a stage II/III group of a population-based validation cohort (n = 85). VD was scored separately in the tumour centre, invasive margin and peritumoral stroma compartments and quantitated as VD/total analysed tissue area or VD/stroma area. RESULTS: High stroma-normalised VD in the invasive margin was associated with significantly longer time to recurrence and overall survival (OS) (p = 0.002 and p = 0.006, respectively) in adjuvant-treated patients of the discovery cohort, but not in surgery-only patients. Stroma-normalised VD in the invasive margin and treatment effect were significantly associated according to a formal interaction test (p = 0.009). Similarly, in the validation cohort, high stroma-normalised VD was associated with OS in adjuvant-treated patients, although statistical significance was not reached (p = 0.051). CONCLUSION: Through the use of novel digitally scored vessel-density-related metrics, this exploratory study identifies stroma-normalised VD in the invasive margin as a candidate marker for benefit of adjuvant 5-FU-based chemotherapy in stage II/III colon cancer. The findings, indicating particular importance of vessels in the invasive margin, also suggest biological mechanisms for further exploration.

  • 8.
    Miranda, Alex
    et al.
    BC Canc, Deeley Res Ctr, Victoria, BC V8R 6V5, Canada.
    Hamilton, Phineas T.
    BC Canc, Deeley Res Ctr, Victoria, BC V8R 6V5, Canada.
    Zhang, Allen W.
    BC Canc, Dept Mol Oncol, Vancouver, BC V5Z 4E6, Canada;BC Childrens Hosp Res Inst, Ctr Mol Med & Therapeut, Vancouver, BC V5Z 4H4, Canada;Univ British Columbia, Grad Bioinformat Training Program, Vancouver, BC V6T 1Z3, Canada.
    Pattnaik, Swetansu
    Garvan Inst Med Res, Kinghorn Canc Ctr, Darlinghurst, NSW 2010, Australia;Garvan Inst Med Res, Canc Div, Darlinghurst, NSW 2010, Australia.
    Becht, Etienne
    Agcy Sci Technol & Res, Singapore Immunol Network, Singapore 138648, Singapore.
    Mezheyeuski, Artur
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Bruun, Jarle
    Oslo Univ Hosp, Norwegian Radium Hosp, Inst Canc Res, Dept Mol Oncol, N-0379 Oslo, Norway.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    de Reynies, Aurelien
    Ligue Natl Canc, Programme Cartes Ident Tumeurs, F-75013 Paris, France.
    Nelson, Brad H.
    BC Canc, Deeley Res Ctr, Victoria, BC V8R 6V5, Canada;Univ Victoria, Dept Biochem & Microbiol, Victoria, BC V8P 3E6, Canada;Univ British Columbia, Dept Med Genet, Vancouver, BC V6T 1Z3, Canada.
    Cancer stemness, intratumoral heterogeneity, and immune response across cancers2019Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, nr 18, s. 9020-9029Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Regulatory programs that control the function of stem cells are active in cancer and confer properties that promote progression and therapy resistance. However, the impact of a stem cell-like tumor phenotype ("stemness") on the immunological properties of cancer has not been systematically explored. Using gene-expression-based metrics, we evaluated the association of stemness with immune cell infiltration and genomic, transcriptomic, and clinical parameters across 21 solid cancers. We found pervasive negative associations between cancer stemness and anticancer immunity. This occurred despite high stemness cancers exhibiting increased mutation load, cancer-testis antigen expression, and intratumoral heterogeneity. Stemness was also strongly associated with cellintrinsic suppression of endogenous retroviruses and type I IFN signaling, and increased expression of multiple therapeutically accessible immunosuppressive pathways. Thus, stemness is not only a fundamental process in cancer progression but may provide a mechanistic link between antigenicity, intratumoral heterogeneity, and immune suppression across cancers.

  • 9.
    Osterman, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Department of Surgery, Gävle Hospital, Gävle, Sweden.
    Mezheyeuski, Artur
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
    Sjöblom, Tobias
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
    Beyond the NCCN Risk Factors in Colon Cancer: An Evaluation in a Swedish Population-Based Cohort2020Ingår i: Annals of Surgical Oncology, ISSN 1068-9265, E-ISSN 1534-4681Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The purpose of this study was to investigate whether pT3-4 and pN-subclassifications, lymph-node ratio (LNR), tumour deposits, pre- and postoperative carcinoembryonic antigen (CEA), and C-reactive protein (CRP)-all parameters commonly collected in clinical management-add information about recurrence risk against a background of routine clinicopathological parameters as defined by the NCCN.

    METHODS: The prospective cohort consisted of all 416 patients diagnosed with colon cancer stage I-III in Uppsala County between 2010 and 2015. Cox proportional hazard models were used to calculate hazard ratios for time to recurrence and overall survival. The results were compared with the entire Swedish population concerning parameters recorded in the national quality registry, SCRCR, during the same time period.

    RESULTS: The Uppsala cohort was representative of the entire Swedish cohort. In unadjusted analyses, pT3-subclassification, pN-subclassification, LNR, tumour deposits, elevated postoperative CEA, and preoperative CRP correlated with recurrence. After adjusting for T-, N-stage, and NCCN risk factors, pN-subclassification, sidedness, and elevated postoperative CEA levels correlated with recurrence. Survival correlated with parameters associated with recurrence, LNR, and elevated postoperative CRP.

    CONCLUSIONS: Additional information on recurrence risk is available from several routinely recorded parameters, but most of the risk is predicted by the commonly used clinicopathological parameters.

  • 10.
    Ruksha, K.
    et al.
    NN Alexandrov Natl Canc Ctr Belarus, Minsk, Byelarus.
    Mezheyeuski, Artur
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Nerovnya, A.
    Belarusian State Med Univ, Pathol, Minsk, Byelarus.
    Bich, T.
    Belarusian State Med Univ, Pathol, Minsk, Byelarus.
    Tur, G.
    Minsk City Clin Oncol Dispensary, Minsk, Byelarus.
    Gorgun, J.
    Belarusian Med Acad Postgrad Educ, Gastroenterol & Nutr, Minsk, Byelarus.
    Luduena, R. F.
    Univ Texas Hlth San Antonio, Biochem, San Antonio, TX USA.
    Portyanko, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. NN Alexandrov Natl Canc Ctr Belarus, Minsk, Byelarus.
    Over‐Expression of the β II Isotype of Tubulin and Especially Its Localization in Cell Nuclei Correlates with Poorer Outcomes in Colorectal Cancer2017Ingår i: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 28, nr 26, s. 3727-3727Artikel i tidskrift (Övrigt vetenskapligt)
  • 11.
    Sarhan, Dhifaf
    et al.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet. Stockholm, Sweden.
    La Fleur, Linnea
    Department of Immunology, Genetics and Pathology, Clinical and experimental pathology, Uppsala, Sweden.
    LI, Shuijie
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet. Stockholm, Sweden.
    Palano, Giorgia
    Department of Medicine, Karolinska University Hospital, Huddinge, Sweden.
    Mezheyeuski, Artur
    Department of Immunology, Genetics and Pathology, Uppsala, Sweden.
    Micke, Patrick
    Department of Immunology, Genetics and Pathology, Clinical and experimental pathology, Uppsala, Sweden.
    Schlisio, Susanne
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet. Stockholm, Sweden.
    Smith, Patrick
    Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, USA.
    Ravetch, Jeffrey
    Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, USA.
    Botling, Johan
    Department of Immunology, Genetics and Pathology, Clinical and experimental pathology, Uppsala, Sweden.
    Karlsson, Mikael C. I.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet. Stockholm, Sweden.
    Antibody targeting of tumor associated macrophages in lung cancer remodel the tumor microenvironment and revives immune targeting of tumor cellsManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Immunotherapy for cancer has revolutionized clinical practice and enabled cures for previously lethal cancers. However, the clinical responses are variable and highly influenced by immune regulatory compartments in the tumor microenvironment. This is especially true for immune-excluded tumors, where clinical trials aiming to recover T cell anti-tumor activity have been disappointing. Thus, in NSCLC and other cancers there is a clinical need for additional and combinatory treatments. We have previously shown that antibodies targeting scavenger receptors expressed on tumor-associated macrophages (TAMs), reduces tumor growth and impair metastasis in murine cancer models. Here we investigated targeting of the scavenger receptor MARCO on human TAMs in NSCLC. We found that expression of this receptor in the tumor correlated with immune-exclusion phenotype. Also, we found that lung cancer cell lines converted healthy myeloid cells towards TAM like cells with high expression of MARCO. These human MARCO+ myeloid cells stopped cytotoxic T cells and natural killer (NK) cells from killing tumors and inhibited their overall activity. We then generated anti-human MARCO antibodies and found that these could repolarize TAMs leading to augmented cytolytic ability of NK cells and T cells to kill tumor cells and recovered their proliferation and IFNγ production capacity. Overall, our data demonstrate that it is feasible to use antibodies to alter human TAM immune suppression of NK and T cell anti-tumor activities.

  • 12.
    Sjöberg, Elin
    et al.
    Karolinska Inst, Dept Oncology Pathol, Stockholm, Sweden.
    Frodin, Magnus
    Karolinska Inst, Dept Oncology Pathol, Stockholm, Sweden.
    Lovrot, John
    Karolinska Inst, Dept Oncology Pathol, Stockholm, Sweden.
    Mezheyeuski, Artur
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Johansson, Martin
    Lund Univ, Dept Lab Med, Lund, Sweden.
    Harmenberg, Ulrika
    Karolinska Inst, Dept Oncology Pathol, Stockholm, Sweden.
    Egevad, Lars
    Karolinska Inst, Dept Oncology Pathol, Stockholm, Sweden.
    Sandstrom, Per
    Karolinska Inst, Dept Oncology Pathol, Stockholm, Sweden.
    Ostman, Arne
    Karolinska Inst, Dept Oncology Pathol, Stockholm, Sweden.
    A minority-group of renal cell cancer patients with high infiltration of CD20+B-cells is associated with poor prognosis2018Ingår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 119, nr 7, s. 840-846Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The role of B-lymphocytes in solid tumours is unclear. Tumour biology studies have implied both anti- and pro-tumoural effects and prognostic studies have mainly linked B-cells to increased survival. This study aimed to analyse the clinical relevance of B-lymphocytes in renal cell cancer (RCC), where information on the prognostic impact is lacking.

    METHODS: Following immunohistochemistry (IHC) stainings with a CD20 antibody, density of CD20+ B-cells was quantified in an RCC discovery-and validation cohort. Associations of B-cell infiltration, determined by CD20 expression or a B-cell gene-signature, and survival was also analysed in 14 publicly available gene expression datasets of cancer, including the kidney clear cell carcinoma (KIRC) dataset.

    RESULTS: IHC analyses of the discovery cohort identified a previously unrecognised subgroup of RCC patients with high infiltration of CD20+ B-cells. The B-cell-high subgroup displayed significantly shorter survival according to uni- and multi-variable analyses. The association between poor prognosis and high density of CD20+ B-cells was confirmed in the validation cohort. Analyses of the KIRC gene expression dataset using the B-cell signature confirmed findings from IHC analyses. Analyses of other gene expression datasets, representing 13 different tumour types, indicated that the poor survival-association of B-cells occurred selectively in RCC.

    CONCLUSION: This exploratory study identifies a previously unrecognised poor-prognosis subset of RCC with high density of CD20-defined B-cells.

  • 13.
    Strell, Carina
    et al.
    Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden.
    Paulsson, Janna
    Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden.
    Jin, Shao-Bo
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden.
    Tobin, Nicholas P.
    Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden.
    Mezheyeuski, Artur
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden.
    Roswall, Pernilla
    Karolinska Inst, Div Vasc Biol, Dept Med Biochem & Biophys, Stockholm, Sweden.
    Mutgan, Ceren
    Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden.
    Mitsios, Nicholas
    Karolinska Inst, Dept Neurosci, Sci Life Lab, Stockholm, Sweden.
    Johansson, Hemming
    Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden.
    Wickberg, Sarah Marie
    Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden.
    Svedlund, Jessica
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden.
    Nilsson, Mats
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden.
    Hall, Per
    Karolinska Inst, Dept Med Epidemiol & Biostat, Solna, Sweden;Soder Sjukhuset, Dept Oncol, Stockholm, Sweden.
    Mulder, Jan
    Karolinska Inst, Dept Neurosci, Sci Life Lab, Stockholm, Sweden.
    Radisky, Derek C.
    Mayo Clin, Comprehens Canc Ctr, Dept Canc Biol, Jacksonville, FL 32224 USA.
    Pietras, Kristian
    Lund Univ, Dept Lab Med, Div Translat Canc Res, Lund, Sweden.
    Bergh, Jonas
    Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden;Karolinska Univ Hosp, Radiumhemmet, Stockholm, Sweden.
    Lendahl, Urban
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden.
    Wärnberg, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Ostman, Arne
    Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden.
    Impact of Epithelial-Stromal Interactions on Peritumoral Fibroblasts in Ductal Carcinoma in Situ2019Ingår i: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 111, nr 9, s. 983-995, artikel-id djy234Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: A better definition of biomarkers and biological processes related to local recurrence and disease progression is highly warranted for ductal breast carcinoma in situ (DCIS). Stromal-epithelial interactions are likely of major importance for the biological, clinical, and pathological distinctions between high- and low-risk DCIS cases. Methods: Stromal platelet derived growth factor receptor (PDGFR) was immunohistochemically assessed in two DCIS patient cohorts (n = 458 and n = 80). Cox proportional hazards models were used to calculate the hazard ratios of recurrence. The molecular mechanisms regulating stromal PDGFR expression were investigated in experimental in vitro co-culture systems of DCIS cells and fibroblasts and analyzed using immunoblot and quantitative real-time PCR. Knock-out of JAG1 in DCIS cells and NOTCH2 in fibroblasts was obtained through CRISPR/Cas9. Experimental data were validated by mammary fat pad injection of DCIS and DCIS-JAG1 knock-out cells (10 mice per group). All statistical tests were two-sided. Results: PDGFR alpha((low))/PDGFR beta((high)) fibroblasts were associated with increased risk for recurrence in DCIS (univariate hazard ratio = 1.59, 95% confidence interval [CI] = 1.02 to 2.46; P = .04 Wald test; multivariable hazard ratio = 1.78, 95% CI = 1.07 to 2.97; P = .03). Tissue culture and mouse model studies indicated that this fibroblast phenotype is induced by DCIS cells in a cell contact-dependent manner. Epithelial Jagged1 and fibroblast Notch2 were identified through loss-of-function studies as key juxtacrine signaling components driving the formation of the poor prognosis-associated fibroblast phenotype. Conclusions: A PDGFR alpha((low))/PDGFR beta((high)) fibroblast subset was identified as a marker for high-risk DCIS. The Jagged-1/Notch2/PDGFR stroma-epithelial pathway was described as a novel signaling mechanism regulating this poor prognosis-associated fibroblast subset. In general terms, the study highlights epithelial-stromal crosstalk in DCIS and contributes to ongoing efforts to define clinically relevant fibroblast subsets and their etiology.

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