Identifying the gut microbe gene products that induce human immune cells to upregulate interferon-gamma production

Document Type

Article

Publication Date

Summer 2021

JAX Location

In: Student Reports, Summer 2021, The Jackson Laboratory

Abstract

Immune checkpoint inhibitors are a type of immunotherapy that serve as a treatment for cancer by enhancing the immune response against cancer cells. The normal function of checkpoint proteins is to turn down the immune response after fighting off infection to prevent immune side effects such as autoimmune disease. However, this can reduce the impact of the immune response against cancer as cancer cells manipulate checkpoint pathways to avoid detection. Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that inhibit the reading of checkpoint proteins and thus enhance the immune response by interfering with the inhibitory signal they induce. Although this can cause autoimmune side effects, it allows T cells to be more effective in killing cancer cells as the body is made more aware of their presence.

Unfortunately, ICIs have very low levels of effectiveness for cancer patients. However, patients that do respond have found treatment to be very successful. Determining what is contributing to a successful response to ICIs would be monumental for this type of immunotherapy. It is predicted that this inter-patient variation can be due to a role the microbiome has in the body’s immune responses. Since microbiome composition varies from person to person, it is likely that not everyone has the appropriate bioactive microbes to respond to ICIs. Higher levels of efficacy after receiving a fecal microbiota transplant from a person who responded to ICIs supports that there may be an intricate relationship between a person’s gut microbiome and their immune system. The relationship between the bacteria in the gut and the immune cells of the body deserve to be looked at more closely. This project aims to elucidate this relationship by examining the production of interferon gamma (IFN‐γ) by activated human peripheral blood mononuclear cells (PBMCs). The goal is to find which microbes are necessary for successful immunotherapy, and to identify what the molecular mechanisms and which microbial gene products may be playing a role in this success.

Through the creation of a fosmid library and execution of transposon mutagenesis, we aim to deduce which gene(s) of Veillonella parvula, Lactobacillus reuteri, and Akkermansia muciniphila, some of the bacteria we had previously identified as involved in ICIs, are responsible for initiating PBMCs to upregulate IFN‐γ production. The impact in understanding this relationship is to make ICIs a more effective and applicable treatment for cancer by supplying patients with probiotics containing these organisms in conjunction with ICI treatment.

Please contact the Joan Staats Library for information regarding this document.

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