Dissecting the interplay between immunoglobulin G and the gut microbiome in cancer progression and metastasis - ABSTRACT Cancer progression and metastasis account for the majority of cancer- related deaths, yet how cancer overcomes the immune system to metastasize is only beginning to be understood. The promise of immunotherapies has underscored how integral the host immune cells are in controlling cancer progression and the critical role of the gut microbiome in modulating responses to immunotherapies. However, we have yet to determine how gut microbiome-immune system interactions modulate cancer metastasis, identify gut microbes associated with metastatic risk, or shift immunotherapy paradigms to proactively attack potential metastases. Recent studies highlighted the role of B cells in immune regulation of tumor progression, as tumor- infiltrating B cells positively associated with improved responses to immunotherapies and favorable prognosis. However, the co-existence of both anti- and pro-tumorigenic B cell populations during cancer progression complicates the approach to studying the functions of tumor-infiltrating B cells. Since immunoglobulin G (IgG) antibodies mediate clearance of pathogens and tumor cells with high affinity and specificity and we recently showed that IgG antibodies target specific gut bacteria, modulating the gut microbiome at steady state, we propose a focused approach to dissect the role of humoral immunity in anti-tumor responses during tumor progression. We hypothesize that the interplay between IgG and gut microbiome will be critical in hindering well defined, sequential steps during tumor progression by shaping the tumor immune microenviroment as well as systemic anti-tumor responses. Thus, we will use a novel model of immunoglobulin G (IgG) deficiency developed by Dr. Zeng to dissect the specific role of IgG production in hindering tumor progression, independent of that of other B cell functions, and to investigate how IgG response to the tumor modulates the gut microbiome and thereby affecting anti-tumor immunity. The role of immunoglobulin G in tumor progression has not yet been systematically evaluated, especially during the pre-metastatic, micro-metastatic or macro- metastatic stages of tumor metastasis. Moreover, the interplay between the gut microbiome and B cell subsets, the development of anti-tumor humoral immunity and memory B cell repertoires remain unexplored. We propose that combining the novel animal model lacking IgG with well characterized tumor models and comprehensive phenotypic and functional characterization of relevant immune subsets will allow this interdisciplinary team to dissect the role of antibodies in cancer progression and determine how the interplay between the gut microbiome and IgG shapes anti-tumor immunity and cancer progression.
