Mechanisms of resistance to anti-TGF-beta therapies in metastatic colorectal cancer
Worldwide Cancer Research
Institute for Research in Biomedicine
Most colorectal cancer (CRC) patients die as a result of metastasis. Neither conventional chemotherapy nor current targeted therapies offer significant benefits once the disease has spread to distant organs. Immune checkpoint inhibitors have shown efficacy in only a small subset of patients bearing hypermutated CRCs. Arguably, these failures result from the incomplete understanding of metastatic CRC, which is in part due to lack of mouse models that recapitulate the advanced stages of the disease. We permuted conditional alleles of the WNT, EGFR, TGF-beta and p53 pathways in intestinal stem cells of mice. Quadruple mutant mice developed metastatic human-like intestinal adenocarcinomas. These tumors display key hallmarks of aggressive CRCs including T cell exclusion and a TGF-beta activated stroma. From these genetic mouse models we derived mouse tumor organoids (MTOs), which upon transplantation in immunocompetent recipients recreated both the primary and metastatic disease. Analysis of metastasis generated by MTOs revealed that tumor cells build an immunoprivileged microenvironment during liver colonization, by promoting T-cell exclusion and blocking the acquisition of a Th1 effector phenotype. Inhibition of TGF-beta signaling reverts this process and unleashes a potent cytotoxic T-cell response against tumor cells, which is long lasting and protects mice from metastatic disease. In mice with progressed liver metastatic disease, blockade of TGF-beta signaling rendered tumors susceptible to anti-PD-1/PD-L1checkpoint therapy. As poor prognosis CRCs are characterized by high levels of TGF-beta and immune evasion, our findings suggest that TGF-beta signaling inhibitors may have broad applications to treat patients with advanced CRC. However, we have discovered that a subset of mouse CRCs develop resistance to TGF-beta-based therapies during metastatic outgrowth. Here we propose to investigate this process and identify the mechanism co-opted by resistant CRCs to evade the action of the adaptive immune system triggered by treatment with TGF-beta inhibitors.
2.1 Biological and endogenous factors