Molecular and Clinical Premises for the Combination Therapy Consisting of Radiochemotherapy and Immunotherapy in Non-Small Cell Lung Cancer Patients

SIMPLE SUMMARY: Immunotherapy is one of the most effective systemic treatment methods for many types of cancers. Unfortunately, cancer cells developed a number of defense mechanisms e.g., the absence of NK cells, macrophages or T lymphocytes in the tumor stroma, lack of pro-inflammatory cytokines in the tumor microenvironment (IL-6, IL-2, IL-12, TNF-alpha), production of immunosuppressive compounds (TGF-beta, indoleamine dioxygenase or neutralization of immune cells through direct immune checkpoints interactions (CD80/CD86 with CTLA-4 and PD-L1 with PD-1) that eventually make treatment ineffective. In this way, non-immunogenic, “cold” tumors are formed. The paper presents those mechanisms in details and focuses on the radiochemotherapy technique which, by neoantigen production, abscopal effect and activation of interferon synthesis pathways (STING), affects the production of cytokines and chemokines and transforms “cold” tumors into highly immunogenic “hot”, inflammatory tumors, susceptible to immunotherapy. Results are based on clinical trials conducted to date, which showed high effectiveness of the combination therapy consisting of radiochemotherapy and immunotherapy in NSCLC patients. ABSTRACT: Non-small cell lung cancer (NSCLC) is one of the most common malignancies around the world. Due to the advanced stage of the disease at the time of diagnosis, most patients require systemic treatment. Immunotherapy with immune checkpoints inhibitors is becoming the main treatment method for many cancers, including NSCLC. Numerous studies have shown greater efficacy of immunotherapy used monoclonal antibodies anti-PD-1 (pembrolizumab and nivolumab) or anti-PD-L1 (atezolizumab and durvalumab) compared to chemotherapy. Unfortunately, cancer cells can develop a number of mechanisms to escape from immune surveillance, including avoidance of cancer cells by the immune system (immune desert), production of immunosuppressive compounds (prostaglandins, IDO, TGF-beta), or direct immune checkpoints interactions. Therapy based on the use of radiochemotherapy with subsequent immunotherapy is becoming the main focus of research in the field of new NSCLC therapies. Radiation therapy stimulates the immune response multidirectionally, affects production of neoantigens and proinflammatory compounds, which transform non-immunogenic (“cold”) tumors into highly immunogenic (“hot”) tumors. As a result, the mechanisms of escape of cancer cells from immune surveillance break down and the effectiveness of immunotherapy increases significantly. The results of clinical trials in this area bring new hope and indicate greater effectiveness of such treatment in terms of prolongation of progression-free survival and overall survival.