Chronic lymphocytic leukaemia induces an exhausted T cell phenotype in the TCL1 transgenic mouse model.
Although chronic lymphocytic leukaemia (CLL) is a B cell malignancy, earlier studies have indicated a role of T cells in tumour growth and disease progression. In particular, the functional silencing of antigen-experienced T cells, called T cell exhaustion, has become implicated in immune evasion in CLL. In this study, we tested whether T cell exhaustion is recapitulated in the TCL1(tg) mouse model for CLL. We show that T cells express high levels of the inhibitory exhaustion markers programmed cell death 1 (PDCD1, also termed PD-1) and lymphocyte-activation gene 3 (LAG3), whereas CLL cells express high levels of CD274 (also termed PD-ligand 1). In addition, the fraction of exhausted T cells increases with CLL progression. Finally, we demonstrate that exhausted T cells are reinvigorated towards CLL cytotoxicity by inhibition of PDCD1/CD274 interaction in vivo. These results suggest that T cell exhaustion contributes to CLL pathogenesis and that interference with PDCD1/CD274 signalling holds high potential for therapeutic approaches.
Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Centre, Paracelsus Medical University, Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
Franz J
FJ
Gassner
Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Centre, Paracelsus Medical University, Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
Nadja
N
Zaborsky
Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Centre, Paracelsus Medical University, Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
Kemal
K
Catakovic
Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Centre, Paracelsus Medical University, Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
Stefan
S
Rebhandl
Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Centre, Paracelsus Medical University, Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
Michael
M
Huemer
Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Centre, Paracelsus Medical University, Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
Alexander
A
Egle
Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Centre, Paracelsus Medical University, Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
Tanja N
TN
Hartmann
Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Centre, Paracelsus Medical University, Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
Richard
R
Greil
Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Centre, Paracelsus Medical University, Salzburg, Austria.|Salzburg Cancer Research Institute, Salzburg, Austria.
Roland
R
Geisberger
D000818:Animals; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics / Q000276:immunology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
D009363:Neoplasm Proteins
PDCD1; T cell exhaustion; chemoimmunotherapy; chronic lymphocytic leukaemia; tumour surveillance