[en] CD226 has been reported to participate in the rescue of CD8+ T cell dysfunction. In this study, we aimed to assess the prognostic value of CD226 in tumor-infiltrating lymphocytes (TILs) derived from colorectal cancer (CRC) liver metastases treated with chemotherapy and radical surgery. TILs from 43 metastases were isolated and analyzed ex vivo using flow cytometry. CD155 and CD3 levels in the tumor microenvironment were assessed by immunohistochemistry. Exploration and validation of biological processes highlighted in this study were performed by bioinformatics analysis of bulk RNA-seq results for 28 CRC liver metastases pretreated with chemotherapy as well as public gene expression datasets. CD226 expression contributes to the definition of the immune context in CRC liver metastases and primary tumors. CD226 on CD8+ T cells was not specifically coexpressed with other immune checkpoints, such as PD1, TIGIT, and TIM3, in liver metastases. Multivariate Cox regression analysis revealed CD226 expression on CD8+ T cells to be an independent prognostic factor (p = 0.003), along with CD3 density at invasion margins (p = 0.003) and TIGIT expression on CD4+ T cells (p = 0.019). CD155 was not associated with the prognostic value of CD226. Gene expression analysis in a validation dataset confirmed the prognostic value of CD226 in CRC liver metastases but not in primary tumors. Downregulation of CD226 on CD8+ TILs in the liver microenvironment was restored by IL15 treatment. Overall, CD226 expression on liver metastasis-infiltrating CD8+ T cells selectively contributes to immune surveillance of CRC liver metastases and has prognostic value for patients undergoing radical surgery.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Viot, Julien ; Department of Medical Oncology, Biotechnology and Immuno-Oncology Platform, University Hospital of Besançon, Besançon, France. jviot@chu-besancon.fr ; INSERM, EFS BFC, UMR1098, RIGHT, University of Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France. jviot@chu-besancon.fr
Abdeljaoued, Syrine; INSERM, EFS BFC, UMR1098, RIGHT, University of Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
Vienot, Angélique; Department of Medical Oncology, Biotechnology and Immuno-Oncology Platform, University Hospital of Besançon, Besançon, France ; INSERM, EFS BFC, UMR1098, RIGHT, University of Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
Seffar, Evan; INSERM, EFS BFC, UMR1098, RIGHT, University of Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
Spehner, Laurie; Department of Medical Oncology, Biotechnology and Immuno-Oncology Platform, University Hospital of Besançon, Besançon, France ; INSERM, EFS BFC, UMR1098, RIGHT, University of Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
Bouard, Adeline; INSERM, EFS BFC, UMR1098, RIGHT, University of Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
Asgarov, Kamal; INSERM, EFS BFC, UMR1098, RIGHT, University of Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
Pallandre, Jean-René; INSERM, EFS BFC, UMR1098, RIGHT, University of Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
Renaude, Elodie ; Université de Liège - ULiège > GIGA > GIGA Cancer - Cancer Signaling ; INSERM, EFS BFC, UMR1098, RIGHT, University of Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
Klajer, Elodie; Department of Medical Oncology, Biotechnology and Immuno-Oncology Platform, University Hospital of Besançon, Besançon, France
Molimard, Chloé; Department of Pathology, University Hospital of Besançon, Besançon, France
Monnien, Franck; Department of Pathology, University Hospital of Besançon, Besançon, France
Bibeau, Frederic; Department of Pathology, University Hospital of Besançon, Besançon, France
Turco, Celia; Department of Surgery, University Hospital of Besançon, Besançon, France
Heyd, Bruno; Department of Surgery, University Hospital of Besançon, Besançon, France
Peixoto, Paul ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases ; INSERM, EFS BFC, UMR1098, RIGHT, University of Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France ; EPIGENEXP platform, University of Bourgogne Franche-Comté, Besançon, France
Hervouet, Eric; INSERM, EFS BFC, UMR1098, RIGHT, University of Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France ; EPIGENEXP platform, University of Bourgogne Franche-Comté, Besançon, France
Loyon, Romain; INSERM, EFS BFC, UMR1098, RIGHT, University of Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
Doussot, Alexandre; Department of Surgery, University Hospital of Besançon, Besançon, France
Borg, Christophe; Department of Medical Oncology, Biotechnology and Immuno-Oncology Platform, University Hospital of Besançon, Besançon, France ; INSERM, EFS BFC, UMR1098, RIGHT, University of Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
Kroemer, Marie; Department of Medical Oncology, Biotechnology and Immuno-Oncology Platform, University Hospital of Besançon, Besançon, France ; INSERM, EFS BFC, UMR1098, RIGHT, University of Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France ; Department of Pharmacy, University Hospital of Besançon, Besançon, France
The authors thank Tumorothèque de Franche Comté for providing tissue samples for this study and Mesocenter de calcul de Franche comte for providing computational power for bioinformatics analysis. The authors thank Ligue contre le cancer and Agecc (Agir ensemble contre le cancer)
for providing financial support for the experiments presented in this study.
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