Intrahepatic CD69+Vδ1 T cells re-circulate in the blood of patients with metastatic colorectal cancer and limit tumor progression
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Intrahepatic CD69+Vδ1 T cells re-circulate in the blood of patients with metastatic colorectal cancer and limit tumor progression. / Bruni, Elena; Cimino, Matteo Maria; Donadon, Matteo; Carriero, Roberta; Terzoli, Sara; Piazza, Rocco; Ravens, Sarina; Prinz, Immo; Cazzetta, Valentina; Marzano, Paolo; Kunderfranco, Paolo; Peano, Clelia; Soldani, Cristiana; Franceschini, Barbara; Colombo, Federico Simone; Garlanda, Cecilia; Mantovani, Alberto; Torzilli, Guido; Mikulak, Joanna; Mavilio, Domenico.
In: J IMMUNOTHER CANCER, Vol. 10, No. 7, e004579, 07.2022.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Intrahepatic CD69+Vδ1 T cells re-circulate in the blood of patients with metastatic colorectal cancer and limit tumor progression
AU - Bruni, Elena
AU - Cimino, Matteo Maria
AU - Donadon, Matteo
AU - Carriero, Roberta
AU - Terzoli, Sara
AU - Piazza, Rocco
AU - Ravens, Sarina
AU - Prinz, Immo
AU - Cazzetta, Valentina
AU - Marzano, Paolo
AU - Kunderfranco, Paolo
AU - Peano, Clelia
AU - Soldani, Cristiana
AU - Franceschini, Barbara
AU - Colombo, Federico Simone
AU - Garlanda, Cecilia
AU - Mantovani, Alberto
AU - Torzilli, Guido
AU - Mikulak, Joanna
AU - Mavilio, Domenico
N1 - © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2022/7
Y1 - 2022/7
N2 - BACKGROUND: More than 50% of all patients with colorectal cancer (CRC) develop liver metastases (CLM), a clinical condition characterized by poor prognosis and lack of reliable prognostic markers. Vδ1 cells are a subset of tissue-resident gamma delta (γδ) T lymphocytes endowed with a broad array of antitumor functions and showing a natural high tropism for the liver. However, little is known about their impact in the clinical outcomes of CLM.METHODS: We isolated human γδ T cells from peripheral blood (PB) and peritumoral (PT) tissue of 93 patients undergone surgical procedures to remove CLM. The phenotype of freshly purified γδ T cells was assessed by multiparametric flow cytometry, the transcriptional profiles by single cell RNA-sequencing, the functional annotations by Gene Ontology enrichment analyses and the clonotype by γδ T cell receptor (TCR)-sequencing.RESULTS: The microenvironment of CLM is characterized by a heterogeneous immune infiltrate comprising different subsets of γδ tumor-infiltrating lymphocytes (TILs) able to egress the liver and re-circulate in PB. Vδ1 T cells represent the largest population of γδ TILs within the PT compartment of CLM that is greatly enriched in Vδ1 T effector (TEF) cells expressing constitutive high levels of CD69. These Vδ1 CD69+ TILs express a distinct phenotype and transcriptional signature, show high antitumor potential and correlate with better patient clinical outcomes in terms of lower numbers of liver metastatic lesions and longer overall survival (OS). Moreover, intrahepatic CD69+ Vδ1 TILs can egress CLM tissue to re-circulate in PB, where they retain a phenotype, transcriptional signature and TCR clonal repertoires resembling their liver origin. Importantly, even the increased frequencies of the CD69+ terminally differentiated (TEMRA) Vδ1 cells in PB of patients with CLM significantly correlate with longer OS. The positive prognostic score of high frequencies of CD69+ TEMRA Vδ1 cells in PB is independent from the neoadjuvant chemotherapy and immunotherapy regimens administered to patients with CLM prior surgery.CONCLUSIONS: The enrichment of tissue-resident CD69+ Vδ1 TEMRA cells re-circulating at high frequencies in PB of patients with CLM limits tumor progression and represents a new important clinical tool to either predict the natural history of CLM or develop alternative therapeutic protocols of cellular therapies.
AB - BACKGROUND: More than 50% of all patients with colorectal cancer (CRC) develop liver metastases (CLM), a clinical condition characterized by poor prognosis and lack of reliable prognostic markers. Vδ1 cells are a subset of tissue-resident gamma delta (γδ) T lymphocytes endowed with a broad array of antitumor functions and showing a natural high tropism for the liver. However, little is known about their impact in the clinical outcomes of CLM.METHODS: We isolated human γδ T cells from peripheral blood (PB) and peritumoral (PT) tissue of 93 patients undergone surgical procedures to remove CLM. The phenotype of freshly purified γδ T cells was assessed by multiparametric flow cytometry, the transcriptional profiles by single cell RNA-sequencing, the functional annotations by Gene Ontology enrichment analyses and the clonotype by γδ T cell receptor (TCR)-sequencing.RESULTS: The microenvironment of CLM is characterized by a heterogeneous immune infiltrate comprising different subsets of γδ tumor-infiltrating lymphocytes (TILs) able to egress the liver and re-circulate in PB. Vδ1 T cells represent the largest population of γδ TILs within the PT compartment of CLM that is greatly enriched in Vδ1 T effector (TEF) cells expressing constitutive high levels of CD69. These Vδ1 CD69+ TILs express a distinct phenotype and transcriptional signature, show high antitumor potential and correlate with better patient clinical outcomes in terms of lower numbers of liver metastatic lesions and longer overall survival (OS). Moreover, intrahepatic CD69+ Vδ1 TILs can egress CLM tissue to re-circulate in PB, where they retain a phenotype, transcriptional signature and TCR clonal repertoires resembling their liver origin. Importantly, even the increased frequencies of the CD69+ terminally differentiated (TEMRA) Vδ1 cells in PB of patients with CLM significantly correlate with longer OS. The positive prognostic score of high frequencies of CD69+ TEMRA Vδ1 cells in PB is independent from the neoadjuvant chemotherapy and immunotherapy regimens administered to patients with CLM prior surgery.CONCLUSIONS: The enrichment of tissue-resident CD69+ Vδ1 TEMRA cells re-circulating at high frequencies in PB of patients with CLM limits tumor progression and represents a new important clinical tool to either predict the natural history of CLM or develop alternative therapeutic protocols of cellular therapies.
KW - Colorectal Neoplasms/immunology
KW - Humans
KW - Immunotherapy
KW - Lymphocytes, Tumor-Infiltrating
KW - Receptors, Antigen, T-Cell, gamma-delta
KW - T-Lymphocyte Subsets/cytology
KW - Tumor Microenvironment
U2 - 10.1136/jitc-2022-004579
DO - 10.1136/jitc-2022-004579
M3 - SCORING: Journal article
C2 - 35863820
VL - 10
JO - J IMMUNOTHER CANCER
JF - J IMMUNOTHER CANCER
SN - 2051-1426
IS - 7
M1 - e004579
ER -