The Immune Niche in the Development of Hematological Malignancies and Implications for Novel Therapy
Tak Mak
PhDPrincess Margaret Cancer Centre, University Health Network
Project Term: October 1, 2022 - September 30, 2027
Our SCOR Program, composed of four complementary Projects supported by three shared Cores, is designed to determine how the immune niche and factors in its composition and regulation affect the initiation and progression of hematopoietic malignancies. Using genetically engineered mouse models, cell cultures and patient samples, the power of multi-omics analyses will be brought to bear to identify common drivers and expose underlying mechanisms. Findings from this work should reveal multiple candidate therapeutic targets whose exploitation may lead to the development of broadly applicable therapeutics for leukemias/lymphomas. Partnerships with pre-clinical and clinical trials experts at our home institutions and beyond will facilitate the translation of our findings to the bedside and potentially provide new hope to patients suffering from these devastating cancers.
Our previous LLS SCOR (2016-2022) revealed that blood cancer cells interact with normal immune cells responding to the attack and affect them in a way promoting tumor progression. This interaction occurs in what is referred to as the “immune niche”. Our 2022-2027 SCOR Program, composed of four Projects supported by three Cores, will investigate how this cooperation happens, and what might disrupt it so that cancer progression is blocked. We will analyze genetically engineered mouse models of blood cancers, cultured cells from these cancers, and patient samples to identify molecules driving interactions in the immune niche and determine how they operate.
Project 1 (Ross Levine) will examine the DNA and proteins of acute myeloid leukemia (AML) cells. AML arises due to mutations of genes in the earliest developing blood cells. Using samples from AML patients and examining single cells at the molecular level, Dr. Levine’s group will identify abnormal combinations of proteins that appear on the surfaces of AML cells but not normal cells. They will then determine if these combinations can be exploited to develop new AML therapies.
Project 2 (Ari Melnick) will examine the DNA and proteins of diffuse large B cell lymphoma (DLBCL). This group will identify the cell actually starting the lymphoma and define the molecular mechanisms that allow DLBCLs to resist current therapies.
Project 3 (Jürgen Ruland) will examine the DNA and proteins of T cell non-Hodgkin lymphoma (T-NHL). Immune responses to this malignancy involve a tumor suppressor protein called PD-1, which acts in an unknown way to prevent T-NHL progression. The Ruland group will investigate how PD-1 acts and also identify other cells and molecules in the T-NHL immune niche that may be therapeutic targets.
Project 4 (Tak Mak) will investigate the DNA sequences of genes whose loss or mutation allows cancerous blood cells to evade anti-tumor immune responses. Abnormal proteins on AML or DLBCL cells will also be identified and their effects on anti-tumor immune responses analyzed. These studies will facilitate future T cell-based immunotherapies.
All four Projects will be supported by Core A (Trevor Pugh) -- DNA, RNA and protein analyses of single cells; Core B (Christopher Mason) -- single cell DNA regulation studies; and Core C (Tak Mak) -- Program administration. Our Projects and Cores should reveal credible molecular targets that can be exploited to generate new treatments for blood cancers.