Increased Coexpression of PD-1, TIGIT, and KLRG-1 on Tumor-Reactive CD8+ T Cells During Relapse after Allogeneic Stem Cell Transplantation

• Published in: Biology of blood and marrow transplantation Vol. 24; no. 4; pp. 666 - 677
• Main Authors: Hutten, Tim J.A., Norde, Wieger J., Woestenenk, Rob, Wang, Ruo Chen, Maas, Frans, Kester, Michel, Falkenburg, J.H. Frederik, Berglund, Sofia, Luznik, Leo, Jansen, Joop H., Schaap, Nicolaas, Dolstra, Harry, Hobo, Willemijn
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2018
• Subjects: Allo-SCT; Allografts; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Female; Gene Expression Regulation, Neoplastic - immunology; Hematologic Neoplasms - immunology; Hematologic Neoplasms - pathology; Hematologic Neoplasms - therapy; Humans; Immunologic Memory; Lectins, C-Type - immunology; Male; MiHA; Neoplasm Proteins - immunology; PD-1; Programmed Cell Death 1 Receptor - immunology; Receptors, Immunologic - immunology; Recurrence; Stem Cell Transplantation; TIGIT and T cells; Trans-Activators - immunology; TIGIT and T cells; MiHA; PD-1; Allo-SCT
• ISSN: 1083-8791; 1523-6536
• DOI: 10.1016/j.bbmt.2017.11.027

•PD-1, TIGIT, and TIM-3 are highly (co)expressed on MiHA-specific CD8+ T cells.•MiHA-specific CD8+ T cells exhibit an early differentiation phenotype.•Relapsed patients' MiHA-specific CD8+ T cells show increased (co)expression of PD-1, TIGIT, and KLRG-1 compared to nonrelapsed patients. Allogeneic stem cell transplantation (allo-SCT) can be a curative treatment for patients with a hematologic malignancy due to alloreactive T cell responses recognizing minor histocompatibility antigens (MiHA). Yet tumor immune escape mechanisms can cause failure of T cell immunity, leading to relapse. Tumor cells display low expression of costimulatory molecules and can up-regulate coinhibitory molecules that inhibit T cell functionality on ligation with their counter-receptors on the tumor-reactive T cells. The aim of this explorative study was to evaluate immune checkpoint expression profiles on T cell subsets and on cytomegalovirus (CMV)- and/or MiHA-reactive CD8+ T cells of allo-SCT recipients using a 13-color flow cytometry panel, and to correlate these expression patterns to clinical outcomes. MiHA-reactive CD8+ T cells exhibited an early differentiated CD27++/CD28++ phenotype with low KLRG-1 and CD57 expression. These T cells also displayed increased expression of PD-1, TIM-3, and TIGIT compared with total effector memory T cells and CMV-specific CD8+ T cells in healthy donors and allo-SCT recipients. Remarkably, high coexpression of PD-1, TIGIT, and KLRG-1 on MiHA-reactive CD8+ T cells was associated with relapse after allo-SCT. Taken together, these findings indicate that MiHA-specific CD8+ T cells of relapsed patients have a distinctive coinhibitory expression signature compared with patients who stay in remission. This phenotype may serve as a potential monitoring tool in patients. Moreover, these findings suggest that PD-1 and TIGIT play important roles in regulating T cell-mediated tumor control, providing a rationale for immunotherapy with blocking antibodies to treat relapse after allo-SCT.