TY - JOUR
T1 - High-dimensional cytometric analysis of colorectal cancer reveals novel mediators of antitumour immunity
AU - De Vries, Natasja L.
AU - Van Unen, Vincent
AU - Ijsselsteijn, Marieke E.
AU - Abdelaal, Tamim
AU - Van Der Breggen, Ruud
AU - Farina Sarasqueta, Arantza
AU - Mahfouz, Ahmed
AU - Peeters, Koen C.M.J.
AU - Höllt, Thomas
AU - Lelieveldt, Boudewijn P.F.
AU - Koning, Frits
AU - De Miranda, Noel F.C.C.
PY - 2019
Y1 - 2019
N2 - Objective: A 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. Design: Thirty-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. Results: We 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 γδT cells with highly similar activated (HLA-DR+CD38+PD-1+) phenotypes. Remarkably, activated γδT cells were almost exclusively found in MMR-deficient cancers. Non-activated counterparts of tumour-resident cytotoxic and γδT cells were present in CRC and healthy mucosa tissues, but not in lymph nodes, with the exception of tumour-positive lymph nodes. Conclusion: This 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.
AB - Objective: A 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. Design: Thirty-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. Results: We 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 γδT cells with highly similar activated (HLA-DR+CD38+PD-1+) phenotypes. Remarkably, activated γδT cells were almost exclusively found in MMR-deficient cancers. Non-activated counterparts of tumour-resident cytotoxic and γδT cells were present in CRC and healthy mucosa tissues, but not in lymph nodes, with the exception of tumour-positive lymph nodes. Conclusion: This 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.
KW - colorectal cancer
KW - immune landscape
KW - innate lymphoid cells
KW - mass cytometry
KW - single-cell immunophenotyping
KW - tissue-resident memory T cells
UR - http://www.scopus.com/inward/record.url?scp=85068611003&partnerID=8YFLogxK
U2 - 10.1136/gutjnl-2019-318672
DO - 10.1136/gutjnl-2019-318672
M3 - Article
AN - SCOPUS:85068611003
SN - 0017-5749
VL - 69 (2020)
SP - 691
EP - 703
JO - Gut
JF - Gut
IS - 4
ER -
