However, many factors contribute to the extent of the response as well as the risk of developing resistance to ICIs in these patients ( 1, 3). Most studies conducted so far have shown that the response to ICIs in M-NSCLC patients is independent of the histological subtype (squamous or non-squamous histology) ( 1, 3). Moreover, there is now evidence that dual blockade of CTLA-4 and PD-1 receptors is sufficient to induce unique cellular responses compared with agents blocking these receptors given alone to M-NSCLC patients ( 20). However, the response to single-agent ICI therapy is not durable, and only a minority of patients have a prolonged benefit ( 2, 9, 14). ICIs have proven to be better tolerated than standard chemotherapy ( 2, 6, 10). The selection of which ICI to use depends on the expression of PD-L1, which can be evaluated using various assays, whose clinical validity has been assessed in numerous clinical trials ( 5, 6, 8– 10, 12– 16). Commonly used ICIs in these patients include the monoclonal antibodies: nivolumab ( 5– 8), pembrolizumab ( 9– 12), durvalumab ( 13), atezolizumab ( 14– 16), and avelumab ( 17), which act by targeting immune checkpoints expressed by tumor infiltrating lymphocytes (TILs)- programmed-death 1 (PD-1)-or expressed by cancer and tumor infiltrating immune cells- programmed-death ligand 1 (PD-L1) ( 18, 19). The availability of immune checkpoint inhibitors (ICIs) has radically changed the management of patients affected by M-NSCLC ( 3). Modulation of interactions between T-cells, antigen-presenting cells, and tumor cells has helped unleash suppressed immune responses and increase the effective elimination of cancer cells ( 1, 2). This key observation has paved the way to the development of immunomodulating agents and opened the era of cancer immunotherapy ( 3), which culminated with the assignment of the Nobel Price to James P. By now, it is clear that the immune system plays a pivotal role not only in eradicating the disease in cancer patients, but also in promoting a long-lasting immunity ( 2). Understanding the interactions between the immune system and cancer cells has greatly advanced our knowledge of the mechanisms of tumor growth and progression ( 1). Immune Checkpoint Inhibitors in Metastatic Non-Small Cell Lung Cancer: An Overview We then discuss the role of genetic and non-genetic ITH on the efficacy of ICIs in patients with M-NSCLC. In this mini review, we first present a brief overview of the use of ICIs in M-NSCLC. Recent observations suggest that spatial heterogeneity in the composition and spatial organization of the tumor microenvironment plays a major role in the response of M-NSCLC patients to ICIs. Intratumor heterogeneity (ITH) at the genetic and phenotypic level is considered as a major cause of anticancer therapy failure, including resistance to ICIs. Unfortunately, approximately 50–75% of patients do not respond to this treatment modality. Immune checkpoint inhibitors (ICIs) represent one of the most promising therapeutic approaches in metastatic non-small cell lung cancer (M-NSCLC). 2Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.1Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland.Marcin Nicoś 1,2* Paweł Krawczyk 1 Nicola Crosetto 2 Janusz Milanowski 1
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