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Review
. 2021 May 25:11:635007.
doi: 10.3389/fonc.2021.635007. eCollection 2021.

Immunotherapy in Treating EGFR-Mutant Lung Cancer: Current Challenges and New Strategies

Kenneth K W To  1 , Winnie Fong  1 , William C S Cho  2
Affiliations
Review

Immunotherapy in Treating EGFR-Mutant Lung Cancer: Current Challenges and New Strategies

Kenneth K W To et al. Front Oncol. .

Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide. Immune checkpoint inhibitors, including monoclonal antibodies against programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1), have dramatically improved the survival and quality of life of a subset of non-small cell lung cancer (NSCLC) patients. Multiple predictive biomarkers have been proposed to select the patients who may benefit from the immune checkpoint inhibitors. EGFR-mutant NSCLC is the most prevalent molecular subtype in Asian lung cancer patients. However, patients with EGFR-mutant NSCLC show poor response to anti-PD-1/PD-L1 treatment. While small-molecule EGFR tyrosine kinase inhibitors (TKIs) are the preferred initial treatment for EGFR-mutant NSCLC, acquired drug resistance is severely limiting the long-term efficacy. However, there is currently no further effective treatment option for TKIs-refractory EGFR-mutant NSCLC patients. The reasons mediating the poor response of EGFR-mutated NSCLC patients to immunotherapy are not clear. Initial investigations revealed that EGFR-mutated NSCLC has lower PD-L1 expression and a low tumor mutational burden, thus leading to weak immunogenicity. Moreover, the use of PD-1/PD-L1 blockade prior to or concurrent with osimertinib has been reported to increase the risk of pulmonary toxicity. Furthermore, emerging evidence shows that PD-1/PD-L1 blockade in NSCLC patients can lead to hyperprogressive disease associated with dismal prognosis. However, it is difficult to predict the treatment toxicity. New biomarkers are urgently needed to predict response and toxicity associated with the use of PD-1/PD-L1 immunotherapy in EGFR-mutated NSCLC. Recently, promising data have emerged to suggest the potentiation of PD-1/PD-L1 blockade therapy by anti-angiogenic agents and a few other novel therapeutic agents. This article reviews the current investigations about the poor response of EGFR-mutated NSCLC to anti-PD-1/PD-L1 therapy, and discusses the new strategies that may be adopted in the future.

Keywords: EGFR mutation; PD-1; PD-L1; immunotherapy; non-small cell lung cancer; targeted therapy; tyrosine kinase inhibitor.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Immunosuppressive tumor microenvironment (TME) in EGFR-mutated NSCLC. EGFR mutations promote an immunosuppressive TME by interfering with several intracellular pathways and modulating immune accessory cells including tumor-infiltrating lymphocytes (TILs), natural killer cells (NK), T-regulatory cells (Tregs), myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Overexpression of CD39/CD73 in EGFR-mutated NSCLC induces high extracellular production and release of adenosine that inhibit the activity of innate and adaptive immune system cells and endothelial cells in TME. Activation of CD39 triggers the de-phosphorylation of ATP to ADP, and subsequently to AMP. On the other hand, CD73 catalyzes the hydrolysis of AMP to adenosine and phosphate. The increased level of extracellular adenosine bind to A2A adenosine receptor (A2AR) expressed by both adaptive and innate immunity, thereby inhibiting the activity of various immune cells. Moreover, exosomes secreted from EGFR-mutated NSCLC cells also increase PD-L1+/CD73+ expression and extracellular adenosine release to promote immunosuppression. IL, interleukin; M2, macrophages 2; ATP, adenosine triphosphate; ADP, adenosine diphosphate; AMP, adenosine monophosphate; CCL2, C-C motif chemokine ligand 2.
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