Immune escape mechanisms have been identified in every step of lung tumorigenesis. A heterogeneous ensemble of immune evasion processes shapes the evolution of precursor lesions towards the invasive phase, contributes to fostering progression from early stage to metastatic disease and defines the main immunological features of specific lung cancer molecular subsets. By disabling distinct phases of the cancer immunity cycle, from antigen presentation to activation of T cell-mediated immunity, and from antigen-specific T cell recruitment to tumor recognition, immune escape in non small cell lung cancer (NSCLC) represents one of the major hurdles to be overcome to improve clinical outcome in patients treated with immunotherapy targeting immune checkpoints.

Development of strong immune evasion has been traditionally associated with the late stages of solid tumor progression, since advanced cancers are more likely to have reached the third phase of the immunoediting process. However, by integrating a variety of approaches, evidence for active immune escape mechanisms has been found even in the pre-invasive lesions that later progress to the main NSCLC histotypes. Pre-invasive lesions of adenocarcinoma (LUAD) and of squamous cell carcinoma (LUSC) can show impaired antigen presentation, loss of heterozygosity at the Human Leukocyte Antigen (HLA) region, neoantigen silencing, activation of immune checkpoints, altered TH1/TH2 cytokine ratios, and immune contexture evolution. Analysis of large panels of LUAD vs. LUSC, of early stage NSCLC vs. normal lung tissue, of specific molecular subsets of NSCLC, and of distinct regions within the same tumor, indicates that all these processes of immune escape continue to evolve in the invasive stage of NSCLC, are associated with inter- and intra-tumor heterogeneity, and contribute to resistance to therapy by immune checkpoint blockade (ICB). In this review, we will discuss the most recent evidence on immune escape mechanisms developing from the precursor to invasive stage in NSCLC, and the contribution of immune evasion to resistance to ICB in lung cancer.