Abstract 6434: A precision probiotic therapeutic promotes a more efficacious type I immune response and limits breast cancer growth in mice
Authors: Cecil Denise L. , Rodmaker Erin , Strenk Susan , Corulli Lauren , Fredricks David N. , Disis Mary L. 
Published: June 2023

High levels of Type I T-cells are needed to eradicate breast cancer. Few cancers induce Type I immunity except those that contain a high mutational burden. The majority of solid tumor patients develop a Type II immune response to commonly recognized tumor antigens, which are aberrantly expressed non-mutated tumor associated proteins. We found that within the amino acid sequence of non-mutated tumor associated antigens are class II binding epitopes that preferentially elicit a T-helper 1 interferon-gamma (g) or an IL-10 T-helper-2 response. We have identified high levels of IL-10 secreting T-cells present in the peripheral blood of both humans and mice, specific for non-mutated tumor antigens, which share significant sequence homologies with bacterial organisms found in the human gut microbiome. These lymphocytes, cross-reactive for both bacterial and tumor antigens (BAC-TA), are enriched for memory T-cells. In mice, the BAC-TA cross-reactive T-cells traffic to tumors and accelerate cancer growth. We have identified a selected number of bacterial species that are most commonly associated with numerous TA homologies (bacteriahigh) and certain species that are rarely homologous to any TA sequences (bacterialow). We hypothesized that bacterialow species can safely be enriched in the gut microbiome. TgMMTV-neu mice, a transgenic model of luminal B murine mammary cancer, pre-treated with vancomycin and metronidazole in the drinking water, received six weekly oral treatments of 109 CFU of a combination of Lactobacillus acidophilus and Ruminococcus albus, both bacterialow species. Metagenomic sequencing of stool examined one week after the last treatment revealed a mean 28% increase in R. albus (p=0.07) and a mean 38% increase in L. acidophilus (p=0.08) as compared to untreated stool. The increase in these two bacterialow species corresponded with ≥30% reduction of 10 bacteriahigh species. This oral treatment regimen also inhibited the growth of a syngeneic ectopic tumor by 36% (p=0.002). Enriching the microbiome with these bacterialow species also enhanced the immunogenicity of a previously reported non-efficacious whole protein vaccine. Immunization with a full-length plasmid-DNA based vaccine targeting IGFBP-2 demonstrated no IFN-g response in control mice (p=0.012). However, after mice were treated with L. acidophilus/R. albus, the full-length vaccine significantly induced IFN-g secretion (p=0.02). These data provide preliminary evidence that reduction of bacteriahigh species can inhibit tumor growth and augment immune responses, providing a basis for using a precision probiotic for the treatment of cancer. Future studies will address whether modulating bacteriahigh species in the gut reduces BAC-TA T-cells in the blood.

Citation Format: Denise L. Cecil, Erin Rodmaker, Susan Strenk, Lauren Corulli, David N. Fredricks, Mary L. Disis. A precision probiotic therapeutic promotes a more efficacious type I immune response and limits breast cancer growth in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6434.