Fetit, R. et al. (2024) Characterising neutrophil subtypes in cancer using scRNA sequencing demonstrates the importance of IL-1β/CXCR2 axis in generation of metastasis specific neutrophils. Cancer Research Communications, 4(2), pp. 588-606. (doi: 10.1158/2767-9764.CRC-23-0319) (PMID:38358352) (PMCID:PMC10903300)
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Abstract
Neutrophils are a highly heterogeneous cellular population. However, a thorough examination of the different transcriptional neutrophil states between health and malignancy has not been performed. We utilized single-cell RNA sequencing of human and murine datasets, both publicly available and independently generated, to identify neutrophil transcriptomic subtypes and developmental lineages in health and malignancy. Datasets of lung, breast, and colorectal cancer were integrated to establish and validate neutrophil gene signatures. Pseudotime analysis was used to identify genes driving neutrophil development from health to cancer. Finally, ligand–receptor interactions and signaling pathways between neutrophils and other immune cell populations in primary colorectal cancer and metastatic colorectal cancer were investigated. We define two main neutrophil subtypes in primary tumors: an activated subtype sharing the transcriptomic signatures of healthy neutrophils; and a tumor-specific subtype. This signature is conserved in murine and human cancer, across different tumor types. In colorectal cancer metastases, neutrophils are more heterogeneous, exhibiting additional transcriptomic subtypes. Pseudotime analysis implicates IL1β/CXCL8/CXCR2 axis in the progression of neutrophils from health to cancer and metastasis, with effects on T-cell effector function. Functional analysis of neutrophil-tumoroid cocultures and T-cell proliferation assays using orthotopic metastatic mouse models lacking Cxcr2 in neutrophils support our transcriptional analysis. We propose that the emergence of metastatic-specific neutrophil subtypes is driven by the IL1β/CXCL8/CXCR2 axis, with the evolution of different transcriptomic signals that impair T-cell function at the metastatic site. Thus, a better understanding of neutrophil transcriptomic programming could optimize immunotherapeutic interventions into early and late interventions, targeting different neutrophil states.
| Item Type: | Articles |
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| Additional Information: | The authors would like to acknowledge and thank the McNab family for generous financial support for this project and the CRUK Scotland Institute's Histology Facility. R. Fetit and C.W. Steele are funded by a UKRI Future Leaders Fellowship (grant no. MR/W007851/1). M. White is funded by the CRUK Clinical Academic Training Programme (grant no. A29706). K. Kirschner is funded by Blood Cancer UK (grant no. 23001), MRC (grant no. MR/W000148/1) and an AMS Springboard Award (#SBF005\1133). A.S. McLaren is funded by CRUK TRACC clinical fellowship (grant no. SEBSTF-2021\100009). J. Falconer is funded by the McNab endowment to the CRUK Scotland Institute and UKRI Future Leaders Fellowship (#MR/W007851/1). M.L. Mills, C.J. Clarke, D. Whyte, X. Cortes-Lavaud, K. Gilroy, T.R.M. Lannagan, R.A. Ridgway, C. Nixon, R. Jackstadt, J. Norman, L.M. Carlin, A.D. Campbell, and O.J. Sansom are funded by CRUK core funding to the CRUK Scotland Institute (A31287), M.L. Mills, X. Cortes-Lavaud, K. Gilroy, T.R.M. Lannagan, R.A. Ridgway, R. Jackstadt, A.D. Campbell, and O.J. Sansom are funded by CRUK Senior Group Leader Programme (A21139 and DRCQQR-May21\100002), C.J. Clarke, D. Whyte, and J. Norman are funded by funded by CRUK Senior Group Leader Programme (A28291) and L.M. Carlin is funded by CRUK Junior Group Leader Programme (A23983). T.R.M. Lannagan, A.D. Campbell, and O.J. Sansom are funded by International Accelerator Award, ACRCelerate, jointly funded by Cancer Research UK (A26825 and A28223), FC AECC (GEACC18004TAB) and AIRC (22795). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Gilroy, Dr Kathryn and Kirschner, Dr Kristina and Nixon, Mr Colin and Fetit, Dr Rana and Campbell, Dr Andrew and Steele, Dr Colin and Mills, Megan and Ridgway, Dr Rachel and Whyte, Declan and White, Dr Mark and Clarke, Dr Cassie and Sansom, Professor Owen and Carlin, Dr Leo and McLaren, Dr Alistair |
| Creator Roles: | Fetit, R.Conceptualization, Data curation, Software, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing McLaren, A.Visualization, Writing – review and editing White, M.Data curation, Visualization, Methodology, Writing – review and editing Mills, M.Data curation, Methodology Gilroy, K.Data curation, Software, Methodology Ridgway, R.Data curation Nixon, C.Resources, Methodology Clarke, C.Writing – review and editing Whyte, D.Writing – review and editing Kirschner, K.Resources, Methodology Carlin, L.Supervision, Visualization, Methodology, Writing – review and editing Campbell, A.Writing – review and editing Sansom, O.Supervision, Funding acquisition, Project administration, Writing – review and editing Steele, C.Conceptualization, Supervision, Funding acquisition, Project administration, Writing – review and editing |
| Authors: | Fetit, R., McLaren, A. S., White, M., Mills, M. L., Falconer, J., Cortes-Lavaud, X., Gilroy, K., Lannagan, T. R.M., Ridgway, R. A., Nixon, C., Naiker, V., Njunge, R., Clarke, C., Whyte, D., Kirschner, K., Jackstadt, R., Norman, J., Carlin, L. M., Campbell, A. D., Sansom, O. J., and Steele, C. W. |
| College/School: | College of Medical Veterinary and Life Sciences College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Cancer Research Communications |
| Publisher: | American Association for Cancer Research |
| ISSN: | 2767-9764 |
| ISSN (Online): | 2767-9764 |
| Published Online: | 29 February 2024 |
| Copyright Holders: | Copyright © 2024 The Authors |
| First Published: | First published in Cancer Research Communications 4(2):588–606 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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