The role of commensal microbiota in shaping systemic anti-tumor immunity /

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Bibliographic Details
Author / Creator:Sivan, Ayelet Shoshana, author.
Ann Arbor : ProQuest Dissertations & Theses, 2015
Description:1 electronic resource (85 pages)
Format: E-Resource Dissertations
Local Note:School code: 0330
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Other authors / contributors:University of Chicago. degree granting institution.
Notes:Includes supplementary digital materials.
Advisors: Thomas F. Gajewski Committee members: Maria-Luisa Alegre; Eugene B. Chang; Nancy J. Cox; Geoffrey Greene.
Dissertation Abstracts International, Volume: 77-05(E), Section: B.
Summary:T cell infiltration of solid tumors is associated with favorable patient outcomes, yet the mechanisms underlying variable endogenous immune responses between individuals are not well understood. Distinct members of the commensal microbiota affect host immunity in various ways, suggesting that differences in the composition of this community may contribute to individual differences in anti-tumor immune responses. In Chapter 1, we examine potential effects of microbial composition on spontaneous anti-tumor immunity, by comparing B16 melanoma growth in C57BL/6 mice having distinct commensal microbiota. The two populations of mice showed robust versus weak spontaneous anti-tumor immunity. Protective responses could be transferred between one mouse population to the other upon cohousing or following fecal transfer, arguing for a microbiota-dependent effect. In Chapter 2 we examine microbial and immunologic mechanisms underlying the observed effects. 16S rRNA sequencing identified Bifidobacterium as associated with the anti-tumor effects. Oral administration of Bifidobacterium alone markedly improved tumor control to the same degree as treatment with systemic PD-L1, in a CD8+ T cell-dependent manner, and combination treatment nearly abolished tumor outgrowth. Mechanistically, the effect was mediated by augmented dendritic cell function leading to more robust antigen-specific CD8+ T cell priming and markedly increased accumulation of activated T cells in the tumor microenvironment. These data support the idea that one source of inter-subject heterogeneity with regard to spontaneous anti-tumor immunity and therapeutic effects of antibodies targeting the PD-1/PD-L1 axis may be the specific composition of gut microbes, which could be manipulated for therapeutic benefit.