Targeting Immunometabolism Mediated by CD73 Pathway in EGFR-Mutated Non-small Cell Lung Cancer: A New Hope for Overcoming Immune Resistance

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.

Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities

“…Immune checkpoint inhibition, including combination anti-PD-1 and anti-CTLA-4 therapy, has shown a distinct lack of efficacy from clinical trials in the TKI resistant setting (26,61). In addition to ongoing efforts to evaluate immunosuppressive targets of the adenosine axis such as the adenosine 2A receptor (A2AR), CD39 and CD73 (66), rational targets for future clinical trials may include IDO, MDSC-depleting strategies such as bevacizumab or selective inhibition of PI3K-gamma.…”

IL-10-Producing ILCs: Molecular Mechanisms and Disease Relevance

“…CD73 is a metabolic immune checkpoint responsible for coordinating the level of extracellular adenosine, which can control the inflammatory response in the microenvironment of tissues that are stressed or damaged ( 47 ). In a variety of tumors, dysregulations of CD73 expression and activity have been reported ( 48 – 50 ). A recent study points out that tumor-infiltrating NK cells up-regulate the expression of CD73, and these CD73 + NK cells will undergo transcriptional reprogramming, and increase the production of IL-10 by up-regulating the transcription activity of STAT3, thereby inhibiting the activity of CD4 + T cells ( 15 ) ( Figure 1 ).…”

A Vismodegib Experience in Elderly Patients with Basal Cell Carcinoma: Case Reports and Review of the Literature

“…The induction of specific molecular pathways, such as Hedgehog signaling cascade mediated by direct genetic modification in tumor cells, or paracrine signaling in the TME, plays an emerging hallmark in several human cancers, including BCC [ 75 , 76 , 77 , 78 ]. Therefore, SMO inhibitors, such as vismodegib and sonidegib, have allowed a revolution in the treatment of advanced BCC, thus, offering a successful therapeutic option for disfiguring and life-threatening disease associated with a long-term clinical benefit.…”