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.