Graduation Year

2024

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Biology (Cell Biology, Microbiology, Molecular Biology)

Major Professor

Eric Lau, Ph.D.

Committee Member

Amer Beg, Ph.D.

Committee Member

Katherine MacNamara, Ph.D.

Committee Member

Eynav Klechevsky, Ph.D.

Committee Member

Paulo Rodriguez, Ph.D.

Keywords

Antigen-presenting cells, Cancer Immunology, Glycosylation, Immunotherapy

Abstract

Since the FDA approval of IL-2 in cancer treatment in the 1980s, immunotherapy has emerged as the standard of care for several tumor types (e.g., melanoma, lung, bladder, colorectal). However, approximately 70 percent of cancer patients, independent of prior treatment or staging, administered immunotherapy will not achieve complete responses and will exhibit disease progression. Several factors have been identified to contribute to treatment failure, including the accumulation of intratumoral immunosuppressive cell populations, insufficient tumor-infiltrating anti-tumor immune populations, or the occurrence of immunoediting on tumor cells. Current strategies to circumvent immunosuppression either lack durable response to new immunosuppressive mechanisms the tumor develops or generate off-target toxicity towards healthy tissue. Therefore, there remains a need for innovative treatment options that can enhance the anti-tumor immune response safely while providing a durable response.

Previously, our group discovered that oral administration of L-fucose decreases tumor growth in melanoma. Further evaluation of this phenomenon reveals that L-fucose-mediated tumor suppression depends on the immune system’s presence, specifically CD4+ T cells. Since CD4+ T cells are crucial for recruiting and activating other intratumoral immune subsets and forming immunological memory, treatment modalities that increase their abundance are expected to promote more robust and durable anti-tumor immune responses. Interestingly, further analysis of the differences in the tumor immune microenvironment of both breast and melanoma tumors reveals that this decrease in tumor volume is associated with an increase in intratumoral immune cells, including subpopulations of dendritic cells, particularly conventional type 1 and monocyte-derived dendritic cells. The intratumoral accumulation of these dendritic cell subtypes and CD4+ T cells suggests a vital role of dendritic cells in facilitating L-fucose-mediated tumor suppression. Additional studies revealed that L-fucose-treated dendritic cells exhibit an enhanced ability to activate T cells. This increase in T cell activation correlates with L-fucose-induced changes in the transcription of critical immunostimulatory and immunomodulatory cytokines in dendritic cells. Furthermore, L-fucose-treated dendritic cells exhibit increased rates of antigen uptake, processing, and presentation, resulting in greater stimulation of T cells.

Together, these data represent the first study, to our knowledge, that suggests L-fucose as a novel adjuvant to enhance the functionality of dendritic cells. As we have shown, L-fucose promotes the polarization of dendritic cell subsets that have previously been used in dendritic cell vaccines (conventional type 1 and monocyte-derived dendritic cells), suggesting that L-fucose has the potential to enhance dendritic cell vaccine efficacy by increasing antigen uptake in dendritic cells to promote more efficient and effective activation of T cells.

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