Immunotherapy Exposes Cancer Stem Cell Resistance and a New Synthetic Lethality

Abstract

Development of resistance to targeted drugs and immunotherapy limits improvement in response rates and disease-free survival of cancer patients. In advanced melanoma, for example, multiple mechanisms of resistance emerge during BRAF inhibitor drug therapy that affect both tumor cell properties and microenvironment.1 In addition, just as immunoediting during the de novo immune response against cancer selects for immune-resistant tumor variants,2 active and passive immunotherapies can create selective pressures that lead to outgrowth of resistant tumor cells or new metastases (Figure 1). Understanding the mechanisms of resistance is critical to developing therapeutic strategies to counteract them as well as preventive measures to avoid their onset. In this issue of Molecular Therapy, Boisgerault and colleagues3 nicely elucidate these points using a tumor vaccination model to induce a T-cell response that places a selective pressure on the tumor facilitating the emergence or selective survival of resistant cancer stem cells or cells undergoing epithelial–mesenchymal transition (EMT). The study further shows how acquired or intrinsic mechanisms of resistance can reveal molecular vulnerabilities that may allow responses even to chemotherapy drugs that would have been considered ineffectual.