Acquired resistance to immunotherapy by physical barriers with cancer cell–expressing collagens in non–small cell lung cancer

Drug resistance is the principal challenge of cancer therapies, including recently developed immunotherapy. More and more popular use of immunotherapy, especially treatments with immune checkpoint inhibitors (ICIs), witnesses explosively increasing cases of both primary and acquired immunotherapy resistance. While primary resistance has been extensively studied, mechanisms underlying acquired resistance of immunotherapy are less understood. Here we reported that tumor cells could develop acquired resistance to ICI treatment through self-built collagen-containing physical barriers in non-small cell lung cancer (NSCLC). We found that tumor cells expressed high levels of multiple collagen genes, including COL3A1 and COL6A1, and were fully covered with collagen fibers. COL3A1 formed a castle-like structure of a cluster of tumor cells and prevented the infiltration of T cells, while COL6A1 seemed to be an armor-like structure of each tumor cell and protected them from attack by cytotoxic T cells. Genetic or pharmaceutic disruption of these collagens, by warfarin, a commonly used medicine, significantly reversed the acquired resistance. Thus, our data reveal an unprecedented tumor cell-intrinsic mechanism, mediated by collagen-containing physical barriers, of acquired immunotherapy resistance, which immediately suggests a treatment option for patients.