Abstract 1778: Bacterial regulation of innate and adaptive tumor immunity in metastatic breast cancer
Authors: Gerbec Zachary , Dedhar Shoukat , Finlay Brett 
Published: July 2021

In the tumor microenvironment (TME), innate and adaptive immune populations produce inflammatory cytokines that, while often critical for anti-tumor immunity, also mediate tumor-promoting functions. This paradoxical role of inflammation highlights the importance of defining the factors that control inflammatory signaling during tumor progression to optimize treatment of inflammation driven tumors and enhance our understanding of the role of inflammation in cancer immunology. Similar to inflammation, recent exploration of bacteria-mediated immune regulation reveals the microbiome mediates both anti-tumor and protumorigenic functions. In breast cancer for example, Helicobacter infection-induced inflammation augments primary tumor growth in a neutrophil-dependent manner. Similarly, an exogenously induced shift toward a more inflammatory microbiome in breast tumor-bearing mice leads to systemic inflammation and myeloid cell infiltration into the tumor that enhances dissemination into the lungs. Considering the lack of surgical options for patients with highly metastatic breast cancer (MBC), we seek to define how microbiome-mediated inflammation affects tumor progression in metastatic forms of the disease. Using a microbiome depletion model, our labs found bacterial depletion inhibited primary tumor growth of metastatic 4T1 breast cancer tumors specifically, while having no effect on non-metastatic 67NR tumors. When we compared immune populations in metastatic and non-metastatic tumors, we found that following microbiome depletion, MHCII expression was significantly reduced on macrophages in metastatic 4T1 tumors specifically. We also found CD4 Th17 populations were decreased both in terms of percentage and number, and that reduced Th17 numbers robustly correlated with reduced tumor volume. We then determined if the decrease in MHCII expression was due to M2 polarization. Analysis of CD206+ cells (M2 macrophages) revealed no differences between macrophages from control and microbiome-depleted animals, and when we analyzed MHCII expression in accordance with CD206, we found that reduced MHCII expression was associated specifically with CD206- cells, showing that down regulation occurs on the M1 population primarily responsible for activating Th17 cells. Additionally, rank correlation analyses revealed that reduced MHCII expression levels robustly correlated reduced tumor volumes in 4T1 tumors. These data suggest the microbiome induces tumor-promoting inflammation in MBC, and suggest a model whereby the microbiome regulates protumorigenic macrophage function by maintaining MHCII expression in MBC, and that bacterial-dependent macrophage activity augments tumor-promoting inflammation from Th17 cells to drive disease progression. Further analysis of this axis will identify pathways that can be targeted during treatment of inflammation-driven tumors.

Citation Format: Zachary Gerbec, Shoukat Dedhar, Brett Finlay. Bacterial regulation of innate and adaptive tumor immunity in metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1778.