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posted on 2024-02-29, 14:21 authored by Rana Fetit, Alistair S. McLaren, Mark White, Megan L. Mills, John Falconer, Xabier Cortes-Lavaud, Kathryn Gilroy, Tamsin R.M. Lannagan, Rachel A. Ridgway, Colin Nixon, Varushka Naiker, Renee Njunge, Cassie J. Clarke, Declan Whyte, Kristina Kirschner, Rene Jackstadt, Jim Norman, Leo M. Carlin, Andrew D. Campbell, Owen J. Sansom, Colin W. Steele Signaling patterns in CRCLM. A and B, Outgoing and incoming signaling patterns in CRCLM. C, Cellular roles as dominant senders (sources) and receivers (targets) in CRCPT and LM. CRCPT dataset did not contain any Tregs or neutrophils. D, UMAP plot of neutrophil subtypes in CRCLM. E, Interaction strength of the global communication patterns between neutrophil, T-cell, and macrophage subtypes. F–I, Outgoing signal strengths from TXNIP+ neutrophils, SPP1+ macrophages, M1- and M2-like macrophages, respectively. J, The contribution of each L-R pair to the overall CXCL signaling pathway among macrophage, neutrophil, and T-cell subtypes. K–M, Visualization of the cell-cell communication patterns mediated by the most significant L-R pairs in CXCL pathway. N, Heat map showing the relative strengths of the significant outgoing and incoming signaling patterns in all communication pathways with dominant sender and receiver immune cell subtypes. The top colored bar plot represents the sum of column of values displayed in the heat map representing the different cell populations. The right gray bar plots represents the sum of row of values, representing the different signaling pathways.
Funding
UK Research and Innovation (UKRI)
Cancer Research UK (CRUK)
Blood Cancer UK
UKRI | Medical Research Council (MRC)
CRUK | Beatson Institute for Cancer Research (The Beatson Institute)
History
ARTICLE 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.
We identify two recurring neutrophil populations and demonstrate their staged evolution from health to malignancy through the IL1β/CXCL8/CXCR2 axis, allowing for immunotherapeutic neutrophil-targeting approaches to counteract immunosuppressive subtypes that emerge in metastasis.
