The Molecular Inflammation Research Group (MIRG) at the University of Tromsø (UiT) – the Arctic University of Norway is allocated to the Department of Clinical Medicine (IKM), and conducts research on cancer biology and treatment, with special emphasis on understanding the biology of the tumor stroma and the immune regulatory potential of radiotherapy.

Cancer-Associated fibroblasts role in lung tumor responses to radiotherapy and immunotherapy

Radiotherapy (RT), together with surgery, constitutes the most efficacious treatment option for most cancer patients. However, despite the proved efficacy of RT, many treated cancer patients suffer from locally recurrent disease and/or metastatic spread of tumor growth. In contrast to the well described cancer-cell intrinsic mechanisms of RT resistance, less knowledge is available on how the stromal components of cancers influence RT outcomes. In this project we aim at unveiling responses of tumor stromal fibroblasts to ionizing radiation, with special emphasize on tumor-growth regulatory effects and immune/inflammatory responses.

Radiotherapy to enhance response rates to immunotherapies

A growing pile of evidences has revealed that local radiotherapy (RT), applied to patients in specific forms, can turn tumors into in situ vaccines. The implementation of radiotherapy to treat cancers refractory to immunotherapy (as monotherapy) has been proposed, but improvements at the clinical front are still very modest. Knowledge from systematic studies at the pre-clinical phase on optimal timing and delivery of RT that could synergize with immunotherapies is still lacking.

In this project we propose to study systematically, in pre-clinical mouse models, the local and systemic immuno-responses elicited by RT applied in different schemes, in order to delineate optimal RT regimens for combinatory immunotherapeutic interventions. Successful personalized immunization of patients with local RT could provide with a simple, widely available and cost-effective means to enhance responses to immunotherapies. Novel data from this project can be directly translated into clinical practice.

Development of novel Immuno-PET tracers for in vivo imaging of tumor-associated immunity (Coastal collaboration-TFS)

Despite the demonstrated effectiveness of immunoregulatory agents such as immune checkpoint blockers (ICB) on refractory cancers, these therapies work satisfactorily only in a reduced subset of patients. Further, ICB treatments are not exempt of risks and are associated to very high costs. Reliable response biomarkers are needed to identify responders and non-responders, and conventional imaging modalities and/or wet biomarkers have not proved adequate. Recently, the immune contexture of the tumor microenvironment was introduced as a new concept that classifies tumors by quantifying immune cell densities and other immune markers, and defines the chances for responding to immunotherapy.  For the case of PD-1/PD-L1 inhibitors, patients are currently stratified by determining tumor expression of the target molecules from a biopsy collected prior treatment. However, the procedure is invasive, introduces risks of tumor cells dissemination and is associated with low sensitivity and specificity due to intratumoral heterogeneity.

Positron emission tomography (PET) is a powerful, quantitative, non-invasive imaging technique that permits longitudinal analyses of biological processes in vivo by administration of a radiolabeled probe. In this project we aim at exploiting PET technology for doing spatial and temporal tracking of intratumoral T lymphocytes and other relevant immune-markers to stratify patients amenable for immunotherapy, and to monitor responses to therapeutic interventions.

Collaborators

Local

Tor Brynjar Stuge, Immunology Research Group, IMB, University of Tromsø

Karen Sørensen, Vascular Biology Research Group, IMB, University of Tromsø

Tom Dønnem, Translational Cancer Research Group, IKM, University of Tromsø

Lill-Tove Busund, Translational Cancer Research Group, IMB, University of Tromsø

Ugo Moens, Molecular INflammation research Group, IMB; UiT

Abhik Ghosh, Department of xchemistry, Faculty for Natural Sciences and technology, UiT

National

Heidi Lyng, Radium Hospitalet, Oslo, Norway

Emmet McCormack, University of Bergen, Norway

Bengt Erik Haug, University of Bergen, Norway

International

Anthony Chalmers, Department of Clinical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK

Arne Østman, Department of Oncology-Pathology Cancer Center Karolinska, Karolinska Institutet Stockholm Sweden

Juan Carlos Rodriguez Manzaneque, University of Granada, Granada, Spain.

Arne Østman, Karolinska Institutett, Sweden

Carina Strell, Uppsala University, Sweden

Lorenzo Galluzzi, Weil Cornell School of Medicine, NY, USA

Publications

1: Li R, Bhandari S, Martinez-Zubiaurre I, Bruun JA, Urbarova I, Smedsrød B,
Simón-Santamaría J, Sørensen KK. Changes in the proteome and secretome of rat
liver sinusoidal endothelial cells during early primary culture and effects of
dexamethasone. PLoS One. 2022 Sep 2;17(9):e0273843. doi:
10.1371/journal.pone.0273843. PMID: 36054185; PMCID: PMC9439253.

2: Hellevik T, Berzaghi R, Lode K, Islam A, Martinez-Zubiaurre I. Immunobiology
of cancer-associated fibroblasts in the context of radiotherapy. J Transl Med.
2021 Oct 18;19(1):437. doi: 10.1186/s12967-021-03112-w. PMID: 34663337; PMCID:
PMC8524905.

3: Berzaghi R, Tornaas S, Lode K, Hellevik T, Martinez-Zubiaurre I. Ionizing
Radiation Curtails Immunosuppressive Effects From Cancer-Associated Fibroblasts
on Dendritic Cells. Front Immunol. 2021 Jun 9;12:662594. doi:
10.3389/fimmu.2021.662594. PMID: 34177901; PMCID: PMC8221608.

4: Berzaghi R, Islam A, Hellevik T, Martinez-Zubiaurre I. Secretion rates and
protein composition of extracellular vesicles released by cancer-associated
fibroblasts after radiation. J Radiat Res. 2021 May 12;62(3):401-413. doi:
10.1093/jrr/rrab018. PMID: 33899109; PMCID: PMC8127688.

5: Yang N, Lode K, Berzaghi R, Islam A, Martinez-Zubiaurre I, Hellevik T.
Irradiated Tumor Fibroblasts Avoid Immune Recognition and Retain
Immunosuppressive Functions Over Natural Killer Cells. Front Immunol. 2021 Jan
22;11:602530. doi: 10.3389/fimmu.2020.602530. PMID: 33584669; PMCID: PMC7874190.

6: Bhandari S, Li R, Simón-Santamaría J, McCourt P, Johansen SD, Smedsrød B,
Martinez-Zubiaurre I, Sørensen KK. Transcriptome and proteome profiling reveal
complementary scavenger and immune features of rat liver sinusoidal endothelial
cells and liver macrophages. BMC Mol Cell Biol. 2020 Nov 27;21(1):85. doi:
10.1186/s12860-020-00331-9. PMID: 33246411; PMCID: PMC7694354.

7: Carrillo-Gálvez AB, Quintero JE, Rodríguez R, Menéndez ST, Victoria González
M, Blanco-Lorenzo V, Allonca E, de Araújo Farias V, González-Correa JE, Erill-
Sagalés N, Martínez-Zubiaurre I, Hellevik T, Sánchez-Hernández S, Muñoz P,
Zurita F, Martín F, Rodríguez-Manzaneque JC, Anderson P. GARP promotes the
proliferation and therapeutic resistance of bone sarcoma cancer cells through
the activation of TGF-β. Cell Death Dis. 2020 Nov 17;11(11):985. doi:
10.1038/s41419-020-03197-z. PMID: 33203838; PMCID: PMC7673987.

8: Hellevik T, Martinez-Zubiaurre I. Alternative biomarkers for immunotherapy.
Tidsskr Nor Laegeforen. 2019 Oct 7;139(14). Norwegian, English. doi:
10.4045/tidsskr.19.0454. PMID: 31592604.

9: Kilvaer TK, Rakaee M, Hellevik T, Vik J, Petris L, Donnem T, Strell C, Ostman
A, Busund LR, Martinez-Zubiaurre I. Differential prognostic impact of platelet-
derived growth factor receptor expression in NSCLC. Sci Rep. 2019 Jul
15;9(1):10163. doi: 10.1038/s41598-019-46510-3. PMID: 31308421; PMCID:
PMC6629689.

10: Berzaghi R, Ahktar MA, Islam A, Pedersen BD, Hellevik T, Martinez-Zubiaurre
I. Fibroblast-Mediated Immunoregulation of Macrophage Function Is Maintained
after Irradiation. Cancers (Basel). 2019 May 17;11(5):689. doi:
10.3390/cancers11050689. PMID: 31108906; PMCID: PMC6562631.

11: Islam A, Urbarova I, Bruun JA, Martinez-Zubiaurre I. Large-scale secretome
analyses unveil the superior immunosuppressive phenotype of umbilical cord
stromal cells as compared to other adult mesenchymal stromal cells. Eur Cell
Mater. 2019 Feb 20;37:153-174. doi: 10.22203/eCM.v037a10. PMID: 30785213.

12: Islam A, Fossum V, Hansen AK, Urbarova I, Knutsen G, Martinez-Zubiaurre I.
In vitro chondrogenic potency of surplus chondrocytes from autologous
transplantation procedures does not predict short-term clinical outcomes. BMC
Musculoskelet Disord. 2019 Jan 10;20(1):19. doi: 10.1186/s12891-018-2380-4.
PMID: 30630436; PMCID: PMC6329094.

13: Martinez-Zubiaurre I, Chalmers AJ, Hellevik T. Radiation-Induced
Transformation of Immunoregulatory Networks in the Tumor Stroma. Front Immunol.
2018 Jul 26;9:1679. doi: 10.3389/fimmu.2018.01679. PMID: 30105016; PMCID:
PMC6077256.

14: Kilvaer TK, Rakaee M, Hellevik T, Østman A, Strell C, Bremnes RM, Busund LT,
Dønnem T, Martinez-Zubiaurre I. Tissue analyses reveal a potential immune-
adjuvant function of FAP-1 positive fibroblasts in non-small cell lung cancer.
PLoS One. 2018 Feb 7;13(2):e0192157. doi: 10.1371/journal.pone.0192157. PMID:
29415055; PMCID: PMC5802915.

15: Islam A, Romijn EI, Lilledahl MB, Martinez-Zubiaurre I. Non-linear optical
microscopy as a novel quantitative and label-free imaging modality to improve
the assessment of tissue-engineered cartilage. Osteoarthritis Cartilage. 2017
Oct;25(10):1729-1737. doi: 10.1016/j.joca.2017.06.008. Epub 2017 Jun 29. PMID:
28668541.

16: Magnussen SN, Hadler-Olsen E, Costea DE, Berg E, Jacobsen CC, Mortensen B,
Salo T, Martinez-Zubiaurre I, Winberg JO, Uhlin-Hansen L, Svineng G. Cleavage of
the urokinase receptor (uPAR) on oral cancer cells: regulation by transforming
growth factor - β1 (TGF-β1) and potential effects on migration and invasion. BMC
Cancer. 2017 May 19;17(1):350. doi: 10.1186/s12885-017-3349-7. PMID: 28526008;
PMCID: PMC5438506.

17: Grinde MT, Vik J, Camilio KA, Martinez-Zubiaurre I, Hellevik T. Ionizing
radiation abrogates the pro-tumorigenic capacity of cancer-associated
fibroblasts co-implanted in xenografts. Sci Rep. 2017 Apr 25;7:46714. doi:
10.1038/srep46714. PMID: 28440285; PMCID: PMC5404232.

18: Eksteen M, Heide G, Tiller H, Zhou Y, Nedberg NH, Martinez-Zubiaurre I,
Husebekk A, Skogen BR, Stuge TB, Kjær M. Anti-human platelet antigen (HPA)-1a
antibodies may affect trophoblast functions crucial for placental development: a
laboratory study using an in vitro model. Reprod Biol Endocrinol. 2017 Apr
21;15(1):28. doi: 10.1186/s12958-017-0245-6. PMID: 28427432; PMCID: PMC5399428.

19: Islam A, Hansen AK, Mennan C, Martinez-Zubiaurre I. Mesenchymal stromal
cells from human umbilical cords display poor chondrogenic potential in
scaffold-free three dimensional cultures. Eur Cell Mater. 2016 May 27;31:407-24.
doi: 10.22203/ecm.v031a26. PMID: 27232667.

20: Gorchs L, Hellevik T, Bruun JA, Camilio KA, Al-Saad S, Stuge TB, Martinez-
Zubiaurre I. Cancer-associated fibroblasts from lung tumors maintain their
immunosuppressive abilities after high-dose irradiation. Front Oncol. 2015 May
12;5:87. doi: 10.3389/fonc.2015.00087. PMID: 26029659; PMCID: PMC4429237.

21: Ben-Batalla I, Cubas-Cordova M, Udonta F, Wroblewski M, Waizenegger JS,
Janning M, Sawall S, Gensch V, Zhao L, Martinez-Zubiaurre I, Riecken K, Fehse B,
Pantel K, Bokemeyer C, Loges S. Cyclooxygenase-2 blockade can improve efficacy
of VEGF-targeting drugs. Oncotarget. 2015 Mar 20;6(8):6341-58. doi:
10.18632/oncotarget.3437. PMID: 25849942; PMCID: PMC4467441.

22: Hansen AK, Indrevik JT, Figenschau Y, Martinez-Zubiaurre I, Sveinbjörnsson
B. Human articular chondrocytes express functional leukotriene B4 receptors. J
Anat. 2015 Mar;226(3):268-77. doi: 10.1111/joa.12275. Epub 2015 Feb 9. PMID:
25677035; PMCID: PMC4337666.

23: Hellevik T, Martinez-Zubiaurre I. Radiotherapy and the tumor stroma: the
importance of dose and fractionation. Front Oncol. 2014 Jan 21;4:1. doi:
10.3389/fonc.2014.00001. PMID: 24478982; PMCID: PMC3896881.

24: Hellevik T, Pettersen I, Berg V, Bruun J, Bartnes K, Busund LT, Chalmers A,
Bremnes R, Martinez-Zubiaurre I. Changes in the Secretory Profile of NSCLC-
Associated Fibroblasts after Ablative Radiotherapy: Potential Impact on
Angiogenesis and Tumor Growth. Transl Oncol. 2013 Feb;6(1):66-74. doi:
10.1593/tlo.12349. Epub 2013 Feb 1. PMID: 23418618; PMCID: PMC3573655.

25: Serrano MJ, Rovira PS, Martínez-Zubiaurre I, Rodriguez MD, Fernández M,
Lorente JA. Dynamics of circulating tumor cells in early breast cancer under
neoadjuvant therapy. Exp Ther Med. 2012 Jul;4(1):43-48. doi:
10.3892/etm.2012.540. Epub 2012 Apr 5. PMID: 23060920; PMCID: PMC3460281.

26: Hellevik T, Pettersen I, Berg V, Winberg JO, Moe BT, Bartnes K, Paulssen RH,
Busund LT, Bremnes R, Chalmers A, Martinez-Zubiaurre I. Cancer-associated
fibroblasts from human NSCLC survive ablative doses of radiation but their
invasive capacity is reduced. Radiat Oncol. 2012 Apr 13;7:59. doi:
10.1186/1748-717X-7-59. PMID: 22500976; PMCID: PMC3359264.

27: Martinez-Zubiaurre I, Annala T, Polacek M. Behavior of Human Articular
Chondrocytes During In Vivo Culture in Closed, Permeable Chambers. Cell Med.
2012 Aug 7;4(2):99-107. doi: 10.3727/215517912X647226. PMID: 26858857; PMCID:
PMC4733830.

28: Serrano Fernádez MJ, Alvarez Merino JC, Martínez Zubiaurre I, Fernández
García A, Sánchez Rovira P, Lorente Acosta JA. Clinical relevance associated to
the analysis of circulating tumour cells in patients with solid tumours. Clin
Transl Oncol. 2009 Oct;11(10):659-68. doi: 10.1007/s12094-009-0421-z. PMID:
19828408.