Targeting PD-L1 and TIGIT could restore intratumoral CD8 T cell function in human colorectal cancer.
Anti-PDL1
Anti-TIGIT
CD8 T cells
Colorectal cancer
TNFα
Journal
Cancer immunology, immunotherapy : CII
ISSN: 1432-0851
Titre abrégé: Cancer Immunol Immunother
Pays: Germany
ID NLM: 8605732
Informations de publication
Date de publication:
Oct 2022
Oct 2022
Historique:
received:
25
10
2021
accepted:
18
02
2022
pubmed:
17
3
2022
medline:
14
9
2022
entrez:
16
3
2022
Statut:
ppublish
Résumé
Microsatellite stable colorectal cancers (MSS-CRC) are resistant to anti-PD-1/PD-L1 therapy but the combination of immune checkpoints inhibitors (ICI) could be a clue to reverse resistance. Our aim was to evaluate ex vivo the capacity of the combination of atezolizumab (anti-PD-L1) and tiragolumab (anti-TIGIT) to reactivate the immune response of tumor infiltrating lymphocytes (TILs) in MSS-CRC. We analysed CRC tumor tissue and the associated blood sample in parallel. For each patient sample, extensive immunomonitoring and cytokine production were tested. We generated an ex vivo assay to study immune reactivity following immune stimulation with checkpoint inhibitors of tumor cell suspensions. Three microsatellite instable (MSI) and 13 MSS-CRC tumors were analysed. To generalize our observations, bioinformatics analyses were performed on public data of single cell RNA sequencing of CRC TILs and RNA sequencing data of TCGA. Atezolizumab alone could only reactivate T cells from MSI tumors. Atezolizumab and tiragolumab reactivated T cells in 46% of MSS-CRC samples. Reactivation by ICK was observed in patients with higher baseline frequency of Th1 and Tc1 cells, and was also associated with higher baseline T cell polyfunctionality and higher CD96 expression. We showed that a high frequency of CD96 expression on T cells could be a surrogate marker of atezolizumab and tiragolumab efficacy. Together these data suggest that the association of atezolizumab and tiragolumab could restore function of CD4 and CD8 TILs in MSS-CRC and could be tested in a clinical trial in colorectal cancer patients with MSS status.
Identifiants
pubmed: 35292828
doi: 10.1007/s00262-022-03182-9
pii: 10.1007/s00262-022-03182-9
doi:
Substances chimiques
Antibodies, Monoclonal
0
Antigens, CD
0
Receptors, Immunologic
0
TIGIT protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2549-2563Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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