High-dimensional cytometric analysis of colorectal cancer reveals novel mediators of antitumour immunity

ObjectiveA comprehensive understanding of anticancer immune responses is paramount for the optimal application and development of cancer immunotherapies. We unravelled local and systemic immune profiles in patients with colorectal cancer (CRC) by high-dimensional analysis to provide an unbiased char...

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Veröffentlicht in:	Gut Jg. 69; H. 4; S. 691 - 703
Hauptverfasser:	de Vries, Natasja L, van Unen, Vincent, Ijsselsteijn, Marieke E, Abdelaal, Tamim, van der Breggen, Ruud, Farina Sarasqueta, Arantza, Mahfouz, Ahmed, Peeters, Koen C M J, Höllt, Thomas, Lelieveldt, Boudewijn P F, Koning, Frits, de Miranda, Noel F C C
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	England BMJ Publishing Group Ltd and British Society of Gastroenterology 01.04.2020 BMJ Publishing Group LTD BMJ Publishing Group
Schriftenreihe:	Original research
Schlagworte:	Antibodies Antigens, CD - metabolism Cancer Cancer immunotherapy Cancer therapies Case-Control Studies CD103 antigen CD38 antigen CD56 antigen CD69 antigen CD7 antigen CD8 Antigens - metabolism Cells Clustering Colon Colonic Neoplasms - immunology Colonic Neoplasms - metabolism Colonic Neoplasms - pathology Colorectal cancer Colorectal carcinoma Cytotoxicity Flow Cytometry Genomics GI cancer Histocompatibility antigen HLA Humans immune landscape Immunity Immunofluorescence Immunogenicity Immunoglobulins Immunotherapy innate lymphoid cells Integrin alpha Chains - metabolism Lymph nodes Lymphatic system Lymphocyte Count Lymphocytes Lymphocytes T Lymphocytes, Tumor-Infiltrating mass cytometry Medical research Metastases Mismatch repair Mucosa Mutation Patients PD-1 protein Peripheral blood Phenotypes Principal components analysis Ribonucleic acid RNA single-cell immunophenotyping tissue-resident memory T cells Transcription Tumors Netherlands immune landscape colorectal cancer single-cell immunophenotyping innate lymphoid cells mass cytometry tissue-resident memory T cells
ISSN:	0017-5749, 1468-3288, 1468-3288
Online-Zugang:	Volltext
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Zusammenfassung:	ObjectiveA comprehensive understanding of anticancer immune responses is paramount for the optimal application and development of cancer immunotherapies. We unravelled local and systemic immune profiles in patients with colorectal cancer (CRC) by high-dimensional analysis to provide an unbiased characterisation of the immune contexture of CRC.DesignThirty-six immune cell markers were simultaneously assessed at the single-cell level by mass cytometry in 35 CRC tissues, 26 tumour-associated lymph nodes, 17 colorectal healthy mucosa and 19 peripheral blood samples from 31 patients with CRC. Additionally, functional, transcriptional and spatial analyses of tumour-infiltrating lymphocytes were performed by flow cytometry, single-cell RNA-sequencing and multispectral immunofluorescence.ResultsWe discovered that a previously unappreciated innate lymphocyte population (Lin–CD7+CD127–CD56+CD45RO+) was enriched in CRC tissues and displayed cytotoxic activity. This subset demonstrated a tissue-resident (CD103+CD69+) phenotype and was most abundant in immunogenic mismatch repair (MMR)-deficient CRCs. Their presence in tumours was correlated with the infiltration of tumour-resident cytotoxic, helper and γδ T cells with highly similar activated (HLA-DR+CD38+PD-1+) phenotypes. Remarkably, activated γδ T cells were almost exclusively found in MMR-deficient cancers. Non-activated counterparts of tumour-resident cytotoxic and γδ T cells were present in CRC and healthy mucosa tissues, but not in lymph nodes, with the exception of tumour-positive lymph nodes.ConclusionThis work provides a blueprint for the understanding of the heterogeneous and intricate immune landscape of CRC, including the identification of previously unappreciated immune cell subsets. The concomitant presence of tumour-resident innate and adaptive immune cell populations suggests a multitargeted exploitation of their antitumour properties in a therapeutic setting.
Bibliographie:	Original article ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0017-5749 1468-3288 1468-3288
DOI:	10.1136/gutjnl-2019-318672