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

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.