| dc.description.abstract | Colorectal cancer (CRC) is characterized by a complex intricate of molecular changes
that accompany morphological alterations, modifying the normal colonic epithelium into
carcinogenic tissue. While the underlying genetic alteration of CRC plays a significant
role, the interplay between the cancer cells and the tumor microenvironment (TME) is a
critical determinant of cancer progression and therapeutic response. In particular, the
immune system interacts in a reciprocal manner with the tumor, regulating its growth
and immune evasion. In recent years, research interest has grown in gut microbiota as
an active component of the TME, highlighting the immunomodulatory role of bacterial-
derived metabolites. Although some of these metabolites have been well-studied, some
of their functions have not been fully described. In fact, the majority of these studies
have been performed in conventional in vitro models, not fully recapitulating the
complexity of the TME and the architecture of the colon epithelium. Here, as a proof of
concept, we investigated the effects of the two well-described metabolites, being
butyrate and deoxycholic acid (DCA), on antigen-specific CD8⁺ T cell function in the
context of murine CRC organoids. We employed conventional co-cultures to model the
tumor-immune-metabolite axis with increasing levels of complexity. Our results
demonstrated that butyrate enhances T cell activation, along with IFN-γ and TNF
production. In contrast, DCA suppressed CD8+ T function, decreasing both cytokine
levels. We also investigated the role of gallic acid (GA), a not-well described phenolic
metabolite. GA exhibited promoting effects on CD8+ T cells, demonstrated by an
decrease in T cell activation. To further study the roles of butyrate and DCA in a more
physiological approach resembling the TME, we used colon-on-chip. This system
mimics the in vivo colon epithelium architecture and functionality. By integrating CRC
organoids and immune cells, we observed that butyrate enhanced the migration of the
immune cells towards the tumor, whereas DCA exhibited an opposite effect. These
findings underscore the necessity of studying immunometabolic interactions in
dynamic, tissue-relevant environment, highlighting the potential for metabolites in
oncology research. | |
