Brain Metastasis Research Group

Members

Dr Mihaela Lorger, Group Leader
Dr. Dario Guglietta, Postdoc
Dr. Sam Heaton, Postdoc
Alca Revalova, Technician
Dr Fiona James, PhD student (MRC Clinical Research Training Fellowship)
Ms Yolanda Kartika, PhD student
Ms Zarnaz Hadi, PhD student (MRC DiMeN DTP)

Research

Understanding the immune system in brain metastases

Cancer cells within primary tumors can spread to distant organs such as the lungs, liver, or the brain, where they establish secondary tumors called metastases. Metastases evolve together with the organ-specific microenvironment. Immune-specialized microenvironment in the brain is characterized by unique anatomic, cellular, and molecular features. Our research aims to understand how immune cells and anti-tumor immune responses are controlled within brain metastases, how they differ to extracranial sites and how they crosstalk with the tumors and immune system outside the brain. We are particularly interested in the immune checkpoint blockade and the mechanisms of resistance to this therapy. Our experimental approaches integrate in vivo and ex vivo models with the analysis of patient-derived tissue.

Harnessing myeloid cells for the delivery of therapies to brain tumors

Myeloid cells originate from hematopoietic stem cells (HSCs) in the bone marrow. They are known to infiltrate brain metastases, where they represent 10-50% of all cells. This high abundance makes them attractive as therapeutic delivery vehicles. We are developing lentiviral HSC gene therapy approaches that utilize an intra-tumoral myeloid cell-specific promoter to drive the expression of therapeutic transgenes. This leads to transgenes expression in HSC-derived myeloid cells following their infiltration into tumors.

Key recent publications

Manuscripts

Natural killer cells are required for the recruitment of CD8+ T cells and the efficacy of immune checkpoint blockade in melanoma brain metastases. Fife C, Williams J, James F, Gregory S, Andreou T, Sunderland A, McKimmie C, Brownlie RJ, Salmond RJ, Heaton S, Errington-Mais F, Hadi Z, Westhead D, Hall M, Davie A, Emmett A, Lorger M. J Immunother Cancer. 2024 Nov 17;12(11):e009522. doi: 10.1136/jitc-2024-009522.

Biglycan and reduced glycolysis are associated with breast cancer cell dormancy in the brain. Sunderland A, Williams J, Andreou T, Rippaus N, Fife C, James F, Dyah Kartika Y, Speirs V, Carr I, Droop A, Lorger M. Front Oncol. 2023 Jun 29;13:1191980. doi: 10.3389/fonc.2023.1191980. eCollection 2023.

Hematopoietic stem cell gene therapy targeting TGFβ enhances the efficacy of irradiation therapy in a preclinical glioblastoma model. Andreou T, Williams J, Brownlie RJ, Salmond RJ, Watson E, Shaw G, Melcher A, Wurdak H, Short SC, Lorger M. J Immunother Cancer. 2021 Mar;9(3):e001143. doi: 10.1136/jitc-2020-001143

Hematopoietic stem cell gene therapy for brain metastases using myeloid cell-specific gene promoters. Andreou T, Rippaus N, Wronski K, Williams J, Taggart D, Cherqui S, Sunderland A, Kartika YD, Egnuni T, Brownlie R, Mathew RK, Holmen SL, Fife C, Droop A, Lorger M J Natl Cancer Inst. 2020 Jun 1;112(6):617-627. doi: 10.1093/jnci/djz181.

Anti-PD-1/anti-CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8+ T cell trafficking. Taggart D, Andreou T, Scott K, Rippaus N, Taggart D, Williams J, Wronski K, Melcher A, Lorger M. Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):E1540-E1549. doi: 10.1073/pnas.1714089115. Epub 2018 Jan 31.

Reviews

Immunotherapy in the context of immune-specialized environment of brain metastases. James F, Lorger M. Discovery Immunology Volume 2, Issue 1, 2023, kyad023, https://doi.org/10.1093/discim/kyad023

Brain metastasis cell lines panel: a public resource of organotropic cell lines. Manuel Valiente, Amanda E.D. Van Swearingen, Carey K. Anders, Amos Bairoch, Adrienne Boire, Paula D. Bos, Diana M. Cittelly, Neta Erez, Gino B Ferraro, Dai Fukumura, Brunilde Gril, Meenhard Herlyn, Sheri L Holmen, Rakesh K. Jain, Johanna A. Joyce, Mihaela Lorger, Joan Massague, Josh Neman, Nicola R Sibson, Patricia S. Steeg, Frits Thorsen, Leonie S. Young, Damir Varešlija, Adina Vultur, Frances Weis-Garcia and Frank Winkler. Cancer Res. 2020 Jul 8:canres.0291.2020. doi: 10.1158/0008-5472.CAN-20-0291. Online ahead of print.PMID: 32641416

Immune Checkpoint Blockade - How Does It Work in Brain Metastases? Lorger M, Andreou T, Fife C, James F. Front Mol Neurosci. 2019 Nov 21;12:282. doi: 10.3389/fnmol.2019.00282. eCollection 2019. Review.

Invited commentary

Taking a swing at TIMP1-armed immunosuppressive astrocytes unleashes T cell immunity against brain metastases. Lorger M* and James F. Cancer Discov. 2025 Jan 13;15(1):11-13. doi: 10.1158/2159-8290.CD-24-1495.