Immune Resistance in Lung Adenocarcinoma

SIMPLE SUMMARY: Lung adenocarcinoma (LUAD) is the major subtype of lung cancer and represents the deadliest human cancer, affecting current-, ex-, and even non-smokers. LUAD is driven by the accumulation of mutations in several different genes, which results in uncontrolled proliferation of the lung cells and the formation of tumors. Our immune system can recognize these transformed cancer cells and start an immune response in order to eliminate them. Unfortunately, cancer cells in turn adapt to and ultimately evade host immune defenses, fostering their growth. Current therapeutic approaches for cancer patients called “immunotherapies” aim to overcome the cancer’s ability to develop mechanisms of resistance to our immune defenses. This review summarizes the mechanisms used by LUAD cancer cells to develop immune resistance and discusses current and future therapeutic approaches in LUAD patient management. ABSTRACT: Lung cancer is the leading cancer killer worldwide, imposing grievous challenges for patients and clinicians. The incidence of lung adenocarcinoma (LUAD), the main histologic subtype of lung cancer, is still increasing in current-, ex-, and even non-smokers, whereas its five-year survival rate is approximately 15% as the vast majority of patients usually present with advanced disease at the time of diagnosis. The generation of novel drugs targeting key disease driver mutations has created optimism for the treatment of LUAD, but, as these mutations are not universal, this therapeutic line benefits only a subset of patients. More recently, the advent of targeted immunotherapies and their documented clinical efficacy in many different cancers, including LUAD, have started to change cancer management. Immunotherapies have been developed in order to overcome the cancer’s ability to develop mechanisms of immune resistance, i.e., to adapt to and evade the host inflammatory and immune responses. Identifying a cancer’s immune resistance mechanisms will likely advance the development of personalized immunotherapies. This review examines the key pathways of immune resistance at play in LUAD and explores therapeutic strategies which can unleash potent antitumor immune responses and significantly improve therapeutic efficacy, quality of life, and survival in LUAD.