Group Kristoffer Hellstrand
The capacity of immune cells to recognize and eliminate malignant cells is compromised in several forms of cancer. Our group studies immune escape in leukemias of myeloid origin with focus on the role of immunosuppressive reactive oxygen species (ROS or “oxygen radicals”). ROS inactivate adjacent lymphocytes by inducing apoptosis, and ROS production by myeloid cells has been forwarded as a mechanism of cancer-related immunosuppression.
Recent studies from our group imply that malignant myeloid cells, recovered from patients with acute or chronic myeloid leukemia, produce ROS as an immune evasion strategy to avoid destruction by anti-leukemic lymphocytes such as natural killer cells or cytotoxic T lymphocytes (outlined below).
Figure 2. Semi-schematic confocal micrograph of a human AML cell [FAB class M4, t(16;16)] with extracellular expression of the NADPH oxidase (green) and surrounded by ROS (red)
Our studies provide insight into the molecular mechanisms of oxidant stress in lymphocytes, and aim to clarify the role of cell-mediated immunity in controlling the malignant clone in myeloid leukemia. In addition, we define new therapeutic targets and new indications for existing anti-leukemic therapies with focus on the use of ROS inhibitors to improve the efficiency of immunotherapy. Members of the group were responsible for the preclinical and clinical development of a ROS inhibitor (Ceplene®), approved for use within EU in 2009, which counteracts leukemia-related immunosuppression in acute myeloid leukemia and prevents life-threatening relapses in this disease.
Research Tools and Resources
The group utilizes advanced cell and molecular technology of relevance to the study of ROS biology, inflammation, hematology, and cancer immunology. The group has initiated and conducted several phase II and phase III clinical trials in leukemia.
Current Group Members
Kristoffer Hellstrand, MD, PhD, Professor
Mats Brune, MD, PhD
Charlotta Movitz, PhD
Ali Akhiani, PhD
Johan Aurelius, PhD
Anna Rydström, PhD
Alexander Hallner, PhD student
Rebecca Riise, PhD student, associated
Ebru Aydin, PhD student, associated
Hanna Grauers Wiktorin, PhD student, associated
- Brune, M., Castaigne, S., Catalano, J., Gehlsen, K., Ho, A., Hofmann, W.H., Hogge, D., Nilsson, B., Or, R., Romero, AI, Rowe, J., Simonsson, B., Spearing, R., Stadtmauer, E., Szer, J., Wallhult, E., Hellstrand, K. (2006) Improved leukemia-free survival after post-consolidation immunotherapy with histamine dihydrochloride and interleukin-2 in acute myeloid leukemia: Results of a randomized phase III trial. Blood, 108: 88-96.
- Thorén FB, Romero AI, Hellstrand K. (2006) Oxygen radicals induce poly(ADP-ribose) polymerase-dependent cell death in cytotoxic lymphocytes. J Immunol., 176: 7301-7.
- Thorén FB, Romero AI, Hermodsson, S., Hellstrand K. (2007) The CD16-/CD56bright subset of natural killer cells is resistant to oxidant-induced cell death. J Immunol, 179: 781-85.
- Thorén FB, Romero AI, Hellstrand K. (2007). Anti-oxidative properties of myeloid dendritic cells: protection of T cells and NK cells from oxygen radical-induced inactivation and apoptosis. J Immunol, 179: 21-5.
- Buyse M, Squifflet P, Lucchesi KJ, Hellstrand K, Brune M, Castaigne S, Rowe JM. (2011) Leukemia-free survival is a surrogate endpoint for overall survival in the evaluation of maintenance therapy for patients with acute myeloid leukemia in complete remission. Haematologica, 96:1106-12.
- Martner A, Aurelius J, Rydström A, Hellstrand K, Thorén FB. (2011) Redox remodeling by dendritic cells protects antigen-specific T cells against oxidative stress. J Immunol., 187:6243-8.
- Aurelius J, Thorén FB, Akhiani A, Brune M, Palmqvist L, Hansson M, Hellstrand K and Martner A. (2011) Monocytic AML cells inactivate anti-leukemic lymphocytes: role of NADPH oxidase/gp91phox expression and the PARP-1/PAR pathway of apoptosis. Blood, in press.
- Aurelius J, Martner A, Brune M, Palmqvist L, Hansson M, Hellstrand K and Thorén FB. (2012) Remission maintenance in acute myeloid leukemia : impact of functional histamine H2 receptors expressed by leukemic cells. Haematologica, in press.
- Aurelius J, Martner A, Romero AI, Riise RE, Palmqvist L, Brune M, Hellstrand K and Thorén FB. (2012) Chronic myeloid leukemic cells trigger poly(ADP-ribose) polymerase-dependent cell death in lymphocytes. J Leukoc Biol, in press.