Dr. Bastian Höchst
Tel +49 89 4140 - 6754
Fax +49 89 4140 - 6922
With more than 14 million new cases and 8.2 million death cases per year, cancer is a primary cause of death worldwide. While chemotherapy has been a mainstay of cancer therapy for many years, innovations in immunology have led to the development of new therapeutic alternatives for chronic diseases including cancer. Considered breakthrough of the year 2013, SCIENCE viewed adoptive T cell therapy of cancer as a most promising approach.
Therapeutic tumor vaccination represents a further promising strategy to induce anti-tumor activity in cancer patients, while generally being well tolerated with only few relevant side effects. Although methods to increase the numbers tumor-specific T cells are continuously advancing, the molecular cues inhibiting tumor specific immunity are still largely unclear. Although circulating tumor-specific T cell are detected in many patients, significant clinical responses with evident tumor regression and improved survival are not directly correlated. This discrepancy may be explained at least in part by lack of infiltration of tumor-specific T cells in tumor tissue. Beyond the ability to localize to tumor tissue, inhibitory cues from the tumor or tumor-associated stromal tissue regulate the functional activity of T cell immunity. Blockade of these checkpoints in co-inhibitory signaling are considered most promising molecular targets in combinatorial immune therapy of cancer. Nevertheless, the key factors that determine successful immune therapy and that allow prediction which subgroup of patients will benefit from such targeted treatment strategies still have to be determined.
Taking into account that immunosuppression is a major contributor for tumor progression, successful tumor vaccines should not only improve CTL responses, but additionally eliminate suppressive factors that hinder anti-tumor immunity. It is well established that certain immune cell populations counteract T cell-based immunotherapy, such as regulatory T cells (Tregs) or myeloid derived suppressor cells (MDSCs). MDSCs represent a heterogenic population of myeloid cells that in mice are defined as CD11b+MHC-II-Ly-6G+Ly-6Clow (Gr-1high) granulocytic MDSCs (CD15+HLA-DR-/low in humans) and CD11b+MHC-II-Ly-6G-Ly-6Chigh (Gr-1low) monocytic MDSCs (CD14+HLA-DR-/low in humans) and can be found under pathological conditions. MDSCs are found in the blood of cancer patients and are associated with the suppression of effector T cell responses, the induction of Tregs and most strikingly, a poor prognosis in cancer patients. Several reports on tumor immunotherapy have suggested that modulating frequencies of immunosuppressive Tregs or MDSCs might improve the effects of tumor vaccination protocols.
We are characterizing the molecular mechanisms that determine the functional plasticity of myeloid cells. Based on a detailed knowledge on the immunobiology of MDSCs we aim to characterize the suppressive network induced by tumors with a particular focus on MDSCs. We have recently shown that MDSCs are generated from mature circulating monocytes by activated stromal cells found in chronically inflamed tissues in a CD44 dependent manner. These monocyte-derived MDSCs are similar to MDSCs found in cancer patients and potently suppress the functionality of activated T cells. We are currently investigating the induction, function and possible molecular targets to deliberately influence the generation and function of MDSCs. Furthermore, we are establishing vaccination protocols to induce a robust immune response and at the same time overcome the limitations of vaccination-induced immunity by concomitant induction of immune-regulatory MDSCs.