Immunotherapy for small cell lung cancer: mechanisms of resistance

Small cell lung cancer (SCLC) is a highly malignant disease with a dismal prognosis that is currently being tested for theclinical activity of checkpoint inhibitors. SCLC is associated with smoking and exhibits a high mutational burden. However, low expression of PD-L1 and MHC antigens, as well low levels of immune cell infiltration and rapid tumor progress seems to limit the efficacy of anticancer immunity. Nevertheless, long-term survival was reported from studies using anti-PD-1/PD-L1 and CTLA-4 agents.Data of clinical trials of checkpoint inhibitors in SCLC show lower success rates compared to NSCLC. The mechanisms of resistance to immunotherapy are discussed for their relevance to SCLC patients.Although some factors, such as a high mutation rate, favor immunotherapy for SCLC patients, downregulation of MHC class I, low expression of PD-L1, poor tumor infiltration by effector T cells, presence of myeloid-derived suppressor cells as well as regulatory T lymphocytes counteract the immune system activation by checkpoint inhibitors. Furthermore, this tumor develops avascular regions which have immunosuppressive effects and restrict access of lymphocytes and antibodies. In conclusion, immunotherapy in SCLC is effective in highly selected patients with good performance status and special and unknown preconditions contributing to long-lasting responses.