DKTK Young Investigator Group "Cancer Immunotherapy" (Dr Borhane Guezguez)
In xenograft AML model, the cancer stem cells (CD45+ CD34+, green) are found either in proximity to the osteoblastic bone marrow niche (osteopontin, red) or across the bone marrow cellular space (DAPI, blue) (courtesy: Dr. Borhane Guezguez) .
Despite biomedical advances, cancer remains the leading cause of mortality worldwide. Immunotherapy is the new promise in effectively combating cancer but still faces clinical challenges. One major hurdle is that tumors generate a disabling immunosuppressive tumor microenvironment that limits the ability of the immune system to act against malignant cells. Particularly, the bone marrow (BM) microenvironment or “niche”, in which adult stem cells are maintained in healthy individuals, has been considered as a source for the development of cancer stem/initiating cells (CSCs) responsible for immune escape and therapy resistance. These CSC immunological attributes remain largely unexplored in hematological malignancies especially in Myelodysplastic syndrome (MDS) and Acute Myeloid Leukemia (AML). The main goal of our research group is to understand the molecular mechanisms responsible for the generation of CSCs in MDS/AML and their role in remodelling the BM niche for cancer immune escape.
Of major interest, we’re focusing on the signalling crosstalk between BM stromal cells, CSCs and immune cells. These processes are mediated in several different ways, for example by soluble factors and cell–cell contact and is suggested to affect chemotherapeutic response, potentially contributing to leukemia relapse. By using multidisciplinary approach grounded in studies with leukemia patient biopsies and xenograft models, we demonstrated that CSCs reside in BM niches in anatomically distinct regions from their normal counterpart. We confirmed that these niches maintain the functional properties of CSCs, contribute to their long-term preservation, and facilitate their resistance to radiotherapy. On the other hand, our lab explores the oncogenic role of signaling pathways in the emergence of CSCs during MDS onset and subsequent transformation to AML. By using stepwise allelic deletion system in mouse models, we established that this gradual leukemia disease progression is governed by the modulation of the activity of GSK-3; a master regulator of WNT/AKT/mTOR pathways. This GSK3-loss dependent lead to a pre-leukemic state with distinctive metabolic alterations and unique CSC epigenetic signatures that can determine human MDS disease risk stratification among clinical cohorts and faithfully predict a patient’s progression to lethal AML for both pediatric and adult cases. With the support of our clinical collaborators, our goal is to study the effect of these metabolic and/or epigenetic dysregulations on the immune system of MDS/AML patients and test their potential in immunomodulating the BM stem cell niche.
From a therapeutic perspective, future development of our discoveries into “nicho-therapies” by targeting CSC-specific markers/signaling pathways and by enhancing immune surveillance may potentially prove useful in selective and effective eradication of Leukemia that could also apply to other type of cancers and their tumor microenvironment.