Abstract
Despite the relevant antitumor efficacy of immunotherapy in advanced non-small cell lung cancer (NSCLC), the results in patients whose cancer harbors activating epidermal growth factor receptor (EGFR) mutations are disappointing. The biological mechanisms underlying immune escape and both unresponsiveness and resistance to immunotherapy in EGFR-mutant NSCLC patients have been partially investigated. To this regard, lung cancer immune escape largely involves high amounts of adenosine within the tumor milieu with broad immunosuppressive effects. Indeed, besides immune checkpoint receptors and their ligands, other mechanisms inducing immunosuppression and including adenosine produced by ecto-nucleotidases CD39 and CD73 contribute to lung tumorigenesis and progression. Here, we review the clinical results of immune checkpoint inhibitors in EGFR-mutant NSCLC, focusing on the dynamic immune composition of EGFR-mutant tumor microenvironment. The adenosine pathway-mediated dysregulation of energy metabolism in tumor microenvironment is suggested as a potential mechanism involved in the immune escape process. Finally, we report the strong rationale for planning strategies of combination therapy with immune checkpoints blockade and adenosine signaling inhibition to overcome immune escape and immunotherapy resistance in EGFR-mutated NSCLC.
Highlights
Primary lung cancer is the most common malignant tumor and the main cause of cancer-related death in the world [1]
High CD73 expression was an independent factor of poor prognosis in terms of overall survival (OS) and recurrence-free survival, exhibiting a remarkably worse prognostic meaning [76]. It is noteworthy the relationship reported by Streicher et al among the epidermal growth factor receptor (EGFR) oncogene activation, the expression of CD73 and the reduced release of IFN-γ in non-small cell lung cancer (NSCLC) cell lines compared to wild-type cells
Immunotherapy combinations are promising strategies aimed at restoring the anti-cancer immunity as well as overcoming innate and adaptive resistance to immune checkpoint inhibitors (ICIs)
Summary
Primary lung cancer is the most common malignant tumor and the main cause of cancer-related death in the world [1]. The use of immune checkpoint inhibitors (ICIs) has revolutionized the management of patients with non-oncogene addicted NSCLC in both first- and second-line settings, showing an unexpected long-term effectiveness and a good toxicity profile [11]; on the other hand, to date the clinical outcomes of ICIs in oncogene-addicted NSCLC are disappointing To this regard, recent clinical studies have described limited efficacy of ICIs, targeting mainly cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed-cell death-1 (PD-1) or its ligand PD-L1, in NSCLC harboring EGFR mutations and TKIs naive [12]. Preclinical studies reported an immune modulatory effect of EGFR signaling by regulating expression of MHC I/II and PD-L1 on tumor cells and the activity of T-cells This suggests a potential synergistic effect for the use of immunotherapy in combination with EGFR-TKIs [42], according to the recent evidence of long-lasting antitumor responses of BRAF/MEK inhibitors with immunotherapy in the treatment of BRAF-mutated metastatic melanoma [43].
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