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A dual TGF-β-driven immunosuppressive mechanism controls T cell recruitment and expansion in metastatic colorectal cancer

ABSTRACT: Poor prognosis colorectal cancer (CRC) is characterized by an immune suppressive TGF-β-activated tumor microenvironment (TME). Pharmacological inhibition of TGF-β signaling promotes T cell infiltration and synergizes with immune checkpoint blockade (ICB) to eliminate metastatic disease in experimental models. Through genetic dissection in model systems and analysis of patient datasets, here we uncover a network of genetic programs regulated by TGF-β signaling in liver metastasis. We show that productive immune responses require both continuous recruitment of tumor-specific CD8+ T cells and subsequent clonal expansion in the TME. TGF-β signaling prevents the recruitment of memory CD8+ T cells by enforcing residence in the lymph nodes. In the absence of newly arrived T cells, the response of tumor-resident T cells to immunotherapy is insufficient to eradicate metastases. We further unveil a genetic program induced by TGF-β in macrophages, which characterizes CRC patients with a high risk of developing metastatic disease. TGF-β-activated macrophages prevent the clonal expansion of newly arrived T cells in the TME through the extracellular matrix protein osteopontin. Overall, our findings reveal how TGF-β signaling integrates immune-suppressive responses in the innate and adaptive immune systems to enable metastatic outgrowth.

ORGANISM(S): Mus musculus

PROVIDER: GSE272376 | GEO | 2025/07/25

REPOSITORIES: GEO

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Project description:Colorectal cancer (CRC) incidence is rising globally and anticipated to become the leading cause of cancer death in younger individuals. Potential risk factors are diet induced obesity and altered microbiomes that lead to accumulation of toxic metabolite accumulation. However, how ammonia and other microbial metabolites impact key signaling pathways, such as TGF-β signaling, to promote CRC remains unclear. Our study investigates a critical link between gut microbiome alterations, ammonia, and their toxic effects on the TGF-β signaling pathway, to drive CRC progression. We found that in an obesity induced mouse model of cancer, altered microbial populations and ammonia promote Caspase-3-mediated cleavage of SMAD3 adaptor βII-spectrin (SPTBN1). Cleaved SPTBN1 fragments form adducts with ammonia to induce pro-inflammatory cytokine expression and alter TGF-β signaling driving CRC. Extending on Alphafold docking simulations, we identified that ammonia interacts with six polar residues at SPTBN1 (S553, Y556, S663, Y666, N986, and T1178) of cleaved SPTBN1 fragments to form hydrogen bonds that disrupt downstream SMAD3 signaling, altering TGF-β signaling to a protumorigenic phenotype. Blocking SPTBN1, through an SPTBN1 specific siRNA blocks ammonia toxicity and restore TGF-β signaling by reducing the abundance of SPTBN1 cleaved fragments. Importantly, SPTBN1 siRNA blocks ammonia toxicity and restore normal TGF-β signaling in CRC cells. Moreover, our research establishes crosstalk between TGF-β signaling and a microbial sensor, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which is significantly overexpressed in CRC patients. We identified CEACAM1-SPTBN1 interactions at specific residues (E517 and Y520) within the immunoreceptor tyrosine-based inhibitory motif (ITIM) of CEACAM1 cytoplasmic domain, with both molecules playing pivotal roles in CRC progression. Our study identifies mechanistic insights into how microbial metabolites target TGF-β a major signaling pathways to promote CRC.

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A dual TGF-β-driven immunosuppressive mechanism controls T cell recruitment and expansion in metastatic colorectal cancer

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