McPherson, Alex
(2024)
Exploring the impact of probiotics and tumor-resident commensal bacteria on cancer.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
Abstract
Cancer remains a main driver of morbidity and mortality worldwide, despite advancements in immunotherapies, which exploit a patient’s immune system to eradicate cancer cells. While immune checkpoint inhibitor (ICI) therapies have demonstrated unprecedented success in patients, only a small subset respond, resulting in a critical need to improve overall efficacy among non-responder patients. With the discovery of the gut microbiome composition influencing immunotherapy response, microbiome modulation has been proposed as a potential adjuvant, particularly via probiotic usage, however the potential anti-tumorigenic effects and the mechanisms of action remain enigmatic. To address this, we investigated the impact of several probiotics and revealed that Lactobacillus reuteri (Lr) is capable of potent tumor restraint in several preclinical cancer models. We elucidated that Lr restrained tumor outgrowth through a critical microbial-host crosstalk between Lr-derived aryl hydrocarbon receptor (AhR) agonist, indole-3-aldehyde (I3A), and CD8 T cells within the tumor microenvironment. This research revealed that Lr translocates to, colonizes, and persists within tumors, where via its released dietary tryptophan metabolite, I3A, it locally promotes interferon-gamma-producing CD8 T cells, thereby enhancing antitumor immunity and ICI efficacy. Moreover, we demonstrated that I3A is necessary and sufficient to drive antitumor immunity, and the loss of AhR signaling within CD8 T cells abrogates Lr’s antitumor effects. We found that a tryptophan-enriched diet is sufficient to potentiate both Lr- and ICI-induced antitumor immunity and required CD8 T cell-intrinsic AhR signaling. Demonstrating the translational relevancy, we provided evidence for a potential role of I3A in promoting ICI efficacy and survival in advanced melanoma patients. Discovering the presence of viable Lr within the tumor led us to further investigate translocation dynamics of commensal bacteria, as translocating microbes may be a potential mechanism by which gut microbiome modulation impacts immunotherapy response. We demonstrated that gut microbial modulation, through fecal microbiota transplants or dietary changes, induces alterations in the tumor microbiome. Both our identification of an impactful, tumor-intrinsic, anti-tumorigenic microbial-host crosstalk and the finding that gut modulation drives changes in the tumor microbiota composition will serve as a foundation for further investigation to explore the impact of various tumor-resident microbes on immunotherapy response in cancer.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
2 January 2024 |
| Date Type: |
Publication |
| Defense Date: |
27 November 2023 |
| Approval Date: |
2 January 2024 |
| Submission Date: |
7 December 2023 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
214 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Infectious Diseases and Microbiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
tumor microenvironment, immunity, probiotics, translocation, microbiome, host-microbial crosstalk |
| Date Deposited: |
02 Jan 2024 21:55 |
| Last Modified: |
02 Jan 2024 21:55 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/45658 |
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Exploring the impact of probiotics and tumor-resident commensal bacteria on cancer. (deposited 02 Jan 2024 21:55)
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