@article{88a5a61bcf224ba29a718dc8f4256476,
title = "Characterising Distinct Migratory Profiles of Infiltrating T-Cell Subsets in Human Glioblastoma",
abstract = "Glioblastoma is the most common and aggressive form of primary brain cancer, with no improvements in the 5-year survival rate of 4.6% over the past three decades. T-cell-based immunotherapies such as immune-checkpoint inhibitors and chimeric antigen receptor T-cell therapy have prolonged the survival of patients with other cancers and have undergone early-phase clinical evaluation in glioblastoma patients. However, a major challenge for T-cell-based immunotherapy of glioblastoma and other solid cancers is T-cell infiltration into tumours. This process is mediated by chemokine-chemokine receptor and integrin-adhesion molecule interactions, yet the specific nature of the molecules that may facilitate T-cell homing into glioblastoma are unknown. Here, we have characterised chemokine receptor and integrin expression profiles of endogenous glioblastoma-infiltrating T cells, and the chemokine expression profile of glioblastoma-associated cells, by single-cell RNA-sequencing. Subsequently, chemokine receptors and integrins were validated at the protein level to reveal enrichment of receptors CCR2, CCR5, CXCR3, CXCR4, CXCR6, CD49a, and CD49d in glioblastoma-infiltrating T-cell populations relative to T cells in matched patient peripheral blood. Complementary chemokine ligand expression was then validated in glioblastoma biopsies and glioblastoma-derived primary cell cultures. Together, enriched expression of homing receptor-ligand pairs identified in this study implicate a potential role in mediating T-cell infiltration into glioblastoma. Importantly, our data characterising the migratory receptors on endogenous tumour-infiltrating T cells could be exploited to enhance the tumour-homing properties of future T-cell immunotherapies for glioblastoma.",
keywords = "chemokine receptors, chemokines, glioblastoma, integrins, migration, scRNA-seq, T cells",
author = "Kollis, {Paris M.} and Ebert, {Lisa M.} and John Toubia and Bastow, {Cameron R.} and Ormsby, {Rebecca J.} and Poonnoose, {Santosh I.} and Sakthi Lenin and Tea, {Melinda N.} and Pitson, {Stuart M.} and Gomez, {Guillermo A.} and Brown, {Michael P.} and Tessa Gargett",
note = "Funding Information: The authors would like to thank Mariana Oksdath Mansilla, Sally Perrin and Kaitlin Scheer (Centre for Cancer Biology) for their assistance in the initial analysis of the scRNA-seq data, Nga Truong and Kristyna Sedivakova (Centre for Cancer Biology) for the isolation of peripheral blood mononuclear cells from glioblastoma patient blood samples, and Erica Yeo (Centre for Cancer Biology) for GNS cell-line culture and supernatant harvesting. Additionally, we thank A/Prof Philip Gregory (Centre for Cancer Biology) for providing human melanoma cell-lines for flow cytometry experiments, Dr Kerrie Foyle (University of Adelaide) for reagents, and A/Prof Craig Wallington-Gates (Flinders Medical Centre) for offering statistical advice. We also acknowledge the support and generosity of the patients and medical and technical staff from SA Pathology and the SA Neurological Tumour Bank (supported by Flinders University, Flinders Foundation and The Neurosurgical Research Foundation), who made collection of tissue specimens possible. scRNA-seq experiments were performed at the Australian Cancer Research Foundation (ACRF) Cancer Genomics and Cancer Discovery Accelerator facilities, established with the generous support of the Australian Cancer Research Foundation. Funding Information: This work was supported by the Neurosurgical Research Foundation, The Hospital Research Foundation Group, a Tour de Cure Senior Research Grant, the Cancer Council SA Beat Cancer Project, the Royal Adelaide Hospital Research Fund, and the Health Services Charitable Gifts Board (Adelaide). scRNA-seq experiments were funded by a Cure Brain Cancer Foundation Infrastructure Grant to SMP, GG, and MB. SMP was supported by the National Health and Medical Research Council of Australia (1156693). GG was supported by the Australian Research Council (FT16010036). PK was supported by a University of Adelaide Honours Scholarship. Funding Information: The authors would like to thank Mariana Oksdath Mansilla, Sally Perrin and Kaitlin Scheer (Centre for Cancer Biology) for their assistance in the initial analysis of the scRNA-seq data, Nga Truong and Kristyna Sedivakova (Centre for Cancer Biology) for the isolation of peripheral blood mononuclear cells from glioblastoma patient blood samples, and Erica Yeo (Centre for Cancer Biology) for GNS cell-line culture and supernatant harvesting. Additionally, we thank A/Prof Philip Gregory (Centre for Cancer Biology) for providing human melanoma cell-lines for flow cytometry experiments, Dr Kerrie Foyle (University of Adelaide) for reagents, and A/Prof Craig Wallington-Gates (Flinders Medical Centre) for offering statistical advice. We also acknowledge the support and generosity of the patients and medical and technical staff from SA Pathology and the SA Neurological Tumour Bank (supported by Flinders University, Flinders Foundation and The Neurosurgical Research Foundation), who made collection of tissue specimens possible. scRNA-seq experiments were performed at the Australian Cancer Research Foundation (ACRF) Cancer Genomics and Cancer Discovery Accelerator facilities, established with the generous support of the Australian Cancer Research Foundation. Publisher Copyright: Copyright {\textcopyright} 2022 Kollis, Ebert, Toubia, Bastow, Ormsby, Poonnoose, Lenin, Tea, Pitson, Gomez, Brown and Gargett.",
year = "2022",
month = apr,
day = "6",
doi = "10.3389/fimmu.2022.850226",
language = "English",
volume = "13",
journal = "Frontiers in Immunology",
issn = "1664-3224",
publisher = "Frontiers Media SA",
}