Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC) - novel approaches and future outlook
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REVIEW
Open Access
Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC) - novel approaches and future outlook Lena Horvath1, Bernard Thienpont2, Liyun Zhao2, Dominik Wolf1,3 and Andreas Pircher1*
Abstract Immunotherapy (IO) has revolutionized the therapy landscape of non-small cell lung cancer (NSCLC), significantly prolonging the overall survival (OS) of advanced stage patients. Over the recent years IO therapy has been broadly integrated into the first-line setting of non-oncogene driven NSCLC, either in combination with chemotherapy, or in selected patients with PD-L1high expression as monotherapy. Still, a significant proportion of patients suffer from disease progression. A better understanding of resistance mechanisms depicts a central goal to avoid or overcome IO resistance and to improve patient outcome. We here review major cellular and molecular pathways within the tumor microenvironment (TME) that may impact the evolution of IO resistance. We summarize upcoming treatment options after IO resistance including novel IO targets (e.g. RIG-I, STING) as well as interesting combinational approaches such as IO combined with antiangiogenic agents or metabolic targets (e.g. IDO-1, adenosine signaling, arginase). By discussing the fundamental mode of action of IO within the TME, we aim to understand and manage IO resistance and to seed new ideas for effective therapeutic IO concepts. Keywords: NSCLC, Immunotherapy resistance, Tumor microenvironment heterogeneity, Targeted therapy
Background Immunotherapy (IO) and particularly immune checkpoint inhibitors (ICI), including programmed death receptor 1 (PD-1) and PD-ligand 1 (PD-L1) inhibitors have revolutionized the treatment landscape of nonsmall cell lung cancer (NSCLC). Previously unanticipated long-term responses in advanced stage disease have been accomplished, with a 5 year overall survival (OS) of 20% in unselected and up to 40% in PD-L1high expressing patients [1]. Despite the striking clinical improvements, the majority of patients eventually fails to respond to ICI therapy due to the evolution of primary or secondary resistance. * Correspondence: [email protected] 1 Internal Medicine V, Department of Hematology and Oncology, Medical University Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria Full list of author information is available at the end of the article
Prospective clinical studies to demonstrate treatment strategies following progression on IO therapy are still lacking. Various IO resistance mechanisms have been characterized, involving tumor cell intrinsic as well as environmental resistance patterns. The tumor microenvironment (TME) plays a critical role by influencing both extrinsic and intrinsic resistance pathways. A better understanding of the heterogenous TME will set stage for further optimizing strategies and guide new avenues in future IO treatment stratification. This review discusses the multitude of novel preclinical and clinical treatment approaches that aim to overcome IO resistance in NSCLC. The
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