Follicular Lymphoma (FL) is a slow-growing cancer of the lymphatic system, which affects one in every three thousand individuals. While existing frontline therapies are effective at suppressing FL, it remains an incurable disease with a median survival of 8-10 years. A fifth of the patients develop resistance to the standard treatment within the first two years. Understanding the mechanisms facilitating resistance and identifying early molecular prognostic indicators remains a high priority. FL tumors have a complex organization, and in addition to the transformed B cells contain a variety of other, non-malignant cell types. It has been demonstrated that the composition of such tumor microenvironment shows significant prognostic association, however the mechanisms and cellular interactions contributing to such association remain unclear. Some portions of the tumor microenvironment may reflect antitumor inflammatory response, while others can facilitate tumor growth. Investigating tumor-microenvironment interactions has been challenging because within the broad cell types that could be readily identified using existing experimental techniques there exist multiple subsets of cells, such as T cells or macrophage subtypes, that can often exert opposing effect. To gain better understanding of the tumor-microenvironment interactions, we will use droplet-based single-cell transcriptomics to perform unbiased characterization of the FL tumors. Examining samples from patients with distinct treatment responses, as well as serial samples before and after chemotherapy, we will quantify cell type composition and capture distinct cell states within each of the identified cell types. Using such detailed descriptions we will identify principal modes of co-variation between FL tumor cells and different aspects of their microenvironment. We will then use more traditional bulk transcriptomic and immunohistochemistry assays to screen larger panels of available FL tumor samples to evaluate the association of the derived molecular signatures with the patient?s progression and response to treatment. In this way the work will aim to provide a detailed molecular description of FL tumor microenvironment and identify potential avenues for disrupting detrimental tumor-microenvironment interactions.

Public Health Relevance

Follicular Lymphoma (FL) is a cancer of the lymphatic system, which despite its slow growth remains incurable with the current therapies. Many of the FL patients quickly develop resistance to therapy or a more aggressive form of a disease, and such progression appears to be linked to the presence of other, non-malignant cells in the FL tumors. Using novel measurement techniques, will examine the detailed composition of the FL tumors at single-cell level, aiming to identify molecular signatures associated the patient?s response to treatment, and suggest potential avenues for disrupting detrimental tumor-microenvironment interactions.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZCA1)
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Read-Connole, Elizabeth Lee
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Harvard Medical School
Schools of Medicine
United States
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