Exploiting tumor metabolism to optimize T cell therapy

PROJECT SUMMARY/ABSTRACT This proposal seeks Dr. Serganova's salary support as a Research Specialist to support Dr. Roberta Zappasodi's research program at Weill Cornell Medicine, Department Hematology and Oncology, to study the role of T-cell responses during immunotherapy in diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common lymphoid neoplasm in adults accounting for ~35% of B-cell non-Hodgkin lymphomas. Despite of relatively good responses to standard treatments, ~40% of patients develop therapy resistance. DLCBLs are genetically heterogeneous and are divided on several subtypes. The MCD-DLBCL subtype is the most clinically aggressive and therapy resistant DLBCL, requiring development of novel therapeutic approaches. One such approach could involve combination with immunotherapy. However, cancer cells evade immune destruction and Dr. Serganova is set to understand the molecular mechanisms of this evasion using her unique experience and expertise in tumor biology, cancer models, and imaging approaches. During previous studies, Dr. Serganova interests were centered on the development of various imaging modalities to understand the complexity of tumor biology in cells and tumors in mice. Recently, in the frame of R50 grant, Dr. Serganova has successfully explored how the modulation of the glycolytic pathway changes the tumor microenvironment and controls the growth of the primary tumors, metastases development, and anti- tumor response during the immunotherapy. Preliminary data acquired during this period show that metabolic deficiencies in tumor cells affect many parameters of the TME, including T cells content and alterations in the vasculature-immune TME compartment with the impact on the tumor vasculature permeability. These studies provide the unique foundation to investigate immunotherapy failures through non-invasive monitoring T cell trafficking, activation and persistence, and understand how interactions between tumor metabolism, microenvironment, targeted antigen expression, and T cell function contribute to evasion of tumor cells from immune destruction. Dr. Serganova is exceptional scientist who has made seminal contributions to the laboratory's research program, including (1) generation of model systems with specific perturbations of metabolic and immune pathways, (2) application of clinically relevant experimental settings in animal studies, and (3) development of advanced imaging technologies. She is continuity, Serganova's immune filling a unique niche within the tha will provide stability, and detailed scientific knowledge to achieve the aims of he NCI-funded grants. Dr. long-time expertise and dedication will advance our understanding of the relationship between system and tumors and will help to develop more effective therapies. Zappasodi laboratory t t