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Lymphomas are a group of heterogeneous blood cancers that arise from lymphocytes. The two primary clinical classifications of lymphomas are Hodgkin's lymphoma (HL), and non-Hodgkin's lymphoma (NHL). In particular, B-cell lymphoma refers to the malignancies originating from different stages of B-cell lymphocyte development. Immunotherapy have yield positive outcome in patients with B-cell lymphoma, however, patients with disseminated cancer might present worst prognosis or relapsed and/or refractory disease. Research on tumor microenvironment (TME) of primary and disseminated cancer has shown a prominent role of inflammation in tumor development. Among the inflammatory molecules associated with cancer survival, cytokines and chemokines are able to attract and activate innate immune cells in the TME. These immune cells can produce a compendium of mediators influencing the TME. However, tumor cells can take advantage of these factors to survive, triggering epithelial-mesenchymal transition (EMT), and aiding in the spread of cancer.Imaging has become an essential technique for the study of cancer, biotherapies, and cancer dissemination. Techniques such as intravital 2-photon microscopy (IV-2PM) enable visualization of cell-to-cell interactions, as well as the study of cell behavior in vivo and in real-time based on complex quantum mechanical effects. With a penetration depth of 100 to 700 µm, IV-2PM is a powerful technique to explore the dynamic behavior of immune cells and cancer dissemination. For this purpose, the sentinel lymph node (sLN), which is the first LN that cancer cells from the primary tumor will invade, is a key organ to study the immune response to cancer dissemination. Due to the limited availability of human disseminated B-cell lymphoma sLN samples, we propose to use a mouse model of disseminated B-cell lymphoma to characterize the mechanisms that lead to the successful dissemination of B-lymphoma cells into the sLN and to identify potential targets that could be suitable for the containment of the disease.I developed a syngeneic B-cell lymphoma mouse model to study the immune response to B-cell lymphoma dissemination in the sLN. I used molecular, cytometric, and microscopy techniques to characterize the inflammatory response to disseminated B-cell lymphoma. Among the most exciting findings, we identified highly elevated protein levels of IL-1a in the lymph of sLN with disseminated B-cell lymphoma, indicating a possible involvement of this cytokine in the spread of B-cell lymphoma. Additionally, we observed a significant decrease in the number of infiltrating B-cell lymphoma cells when NK1.1 expressing cells are depleted. We hypothesize that chronic inflammation, possibly associated with IL-1a expression, was changing the phenotype of NK cells to have a pro-tumor effect in the sLN. We also used IV-2PM to measure cell action differences between NK cells in homeostatic sLN vs. sLN with cancer dissemination.Overall, this work stresses the importance of studying the effect of inflammation on the B-cell lymphoma dissemination in the sLN. Findings from this work will increase our knowledge of the mechanisms that underlie the lymphatic dissemination of B-cell lymphoma and its interaction with immune cells and the stromal compartment in the sLN. We foresee that this research provides valuable information for developing new therapeutic approaches to contain the spread of B-cell lymphoma.
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