Thymic microenvironment in T-cell leukemia development

T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) are very aggressive cancers that arise from immature T cells developing within the thymic microenvironment. There is ample evidence showing that the molecular crosstalk between thymocytes and microenvironmental cells can promote leukemogenesis. One notable example is the expression of lymphotoxin proteins by emerging leukemic T cells and the stimulation of their receptor, lymphotoxin-β receptor, in stromal cells. The LTβR activates several pathways, prominently the NF-κB signaling pathway, so it will be important to uncover how LTβR relays signals promoting leukemia development.

What are the long-lasting impacts of T-cell leukemia and lymphoma on microenvironmental cells?

At the peak of disease, T-LBL and T-ALL overwhelm the organs where they expand, the thymus and bone marrow, respectively. It is not known if these organs recover to their full extent, when patients are cured from these diseases, so we aim to shed light on the extent and nature of cellular microenvironmental alterations in survivor individuals. We have developed mouse models that can both develop and be cured from leukemia or lymphoma, and that will enable the identification of cellular persistent damage attributed to the previous burdensome presence of leukemic cells. This achievement will provide valuable insights into the long-term effects of these blood cancers and potentially inform the development of new therapeutic strategies.

T-cell receptor signaling in T-cell leukemia

The T-cell receptor plays a central role for T cell development and immune function. Its role in T-cell leukemia remains to be fully understood. There is evidence pointing to a role in promoting leukemogenesis and leukemic cell dissemination. Counterintuitively, TCR stimulation has also been shown to induce leukemic T cell apoptosis. We are investigating how this receptor can play this dual role in disease and how can this knowledge be translated into therapeutic strategies.

PSGL-1 as an immunotherapeutic target in lymphoma

P-selectin glycoprotein ligand-1 (PSGL-1) is as a novel immunotherapeutic target for lymphoma. Besides being an adhesion molecule involved in malignant cell migation and infiltration to favorable niches, PSGL-1 promotes T cell exhaustion and thus ineffective response to tumor antigens. We are exploring the potential of blocking the PSGL-1 immune checkpoint function with antibodies, with the aim of increasing the activation of lymphoma-infiltrating T cells. Further research will determine how PSGL-1 antibody treatment remodels the lymphoma microenvironment immune landscape.