Author ORCID Identifier

0000-0001-8917-9462

Date of Graduation

5-2021

Document Type

Dissertation (PhD)

Program Affiliation

Immunology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Jennifer A Wargo, MD, MMSc

Committee Member

James P Allison, PhD (co-advisor)

Committee Member

Stephanie Watowich, PhD

Committee Member

Robert Jenq, MD

Committee Member

Nadim Ajami, PhD

Abstract

Cancer is a disease with only one degree of separation, affecting one in two men and one in three women in their lifetimes; accounting for 1 of every 6 deaths. While cancer mortality rates continue to improve, incidence rates are expected to rise and shift through 2050 due to epidemiological and demographic transitions worldwide. As such, it is imperative to continue to investigate and improve our understanding of both disease etiology and hallmarks of response to treatment. Currently, conventional therapies include, but are not limited to, surgery, chemotherapy, and radiotherapy. However, within the past decade, major advances have been made in cancer treatment using immunotherapy. Immunotherapy encompasses several classes of therapeutics and is an exceptional type of precision medicine that leverages the power of the human immune system to fight disease. In this way, it affords robust treatment choices for patients thought to have intractable disease. One specific type of immunotherapy shown to have a significant clinical benefit for cancer patients is monoclonal antibody immune checkpoint blockade (ICB). ICB removes inhibitory signals of T cell activation which enables tumor-reactive T cells to overcome regulatory mechanisms and mount an effective antitumor response.

Despite significant clinical gains in the setting of ICB treatment, limitations to this therapeutic strategy have inevitably surfaced as they have for prior generations of therapeutic strategies. Efforts are underway to better understand the molecular and immune mechanisms of therapeutic response and resistance in the context of ICB, and recent work has moved the field forward in this regard. One area of medical research that aims to improve clinical response of ICB is the gut microbiome. The microbiome is defined as the community of commensal bacteria, fungi, and viruses, both good and bad, that co-habits the human body. This dissertation is focused on the role of gut microbiome in shaping response and resistance to cancer therapy. More specifically, this work follows up on preclinical studies that suggest that the gut microbiome modulates tumor response to ICB. At the time, these studies had not yet been well characterized in human cancer patients.

To address this gap in knowledge we prospectively collected gut microbiome and immune samples from patients with metastatic melanoma starting treatment with anti–PD-1 therapy. Interesting, the clinical assessment of gut, tumor, and immune profiling suggested gut microbiome composition and immunity correlated with patient response to ICB. To understand this further, we designed preclinical murine studies to gain further insights into the immune mechanisms through which the gut microbiome impacted response to ICB. Key differences were found in responders and non-responders. Specifically, responders had greater microbiome diversity and a significantly higher number of helper and killer T cells in their tumor microenvironment; when compared to non-responders. Additionally, responders were found to have higher systemic anti-cancer signaling molecules interferon-gamma and interleukin-2. Together, these findings were the first of their kind, highlighting the impact of the composition of the gut microbiome and the role of host immunity on patient response to anti-cancer immunotherapy.

In parallel to our work in evaluating how the gut microbiome modulates response to checkpoint blockade, we also examined how external lifestyle factors influence the health of the gut microbiome. To decipher these complexities, we assessed fecal microbiota profiles, dietary habits, and over-the-counter (OTC) probiotic use in a cohort of melanoma patients. Again, we observed substantial differences in gut microbiota between responders (R) and on-responders (NR); as well as distinct microbiome composition between patients with melanoma and healthy donors. Notably, distinct patient dietary habits- low fiber intake and OTC probiotic use- correlated with decreased response to ICB, decreased microbiome diversity, and shortened progression-free survival (PFS). These findings were recapitulated in preclinical mouse models designed to reflect patient fiber intake and probiotic use. Across these two tumor models, we show that dietary and lifestyle factors can negatively affect ICB through a coordinated suppression of CD8 and CD4+ IFNg T cells in the tumor microenvironment.

Taken together, this work evaluated factors within the wider immune milieu that contribute, in collaboration with the gut microbiome, to the success of immune checkpoint blockade. Additionally, we assessed the broader patient environment, intrinsic and extrinsic, thought to shape the composition of the gut microbiome and thereby the patient’s anti-tumor response. Collectively, we show how the gut microbiome influences local and systemic immune response systems potentiating an anti-tumor response. These lines of research have provided new insights as to how we might better target, track, and prevent cancer. Moreover, given the ‘immune’ similarities cancer shares with a number of other chronic maladaptive states this research looks to have a broader impact on chronic inflammatory diseases such arthritis, type I diabetes, neurodegenerative disorders, and infectious diseases such as COVID-19.

Keywords

immunology, cancer, microbiome, translational oncology, immune checkpoint blockade, immunotherapy, biomedicine

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