Upregulation of PD-L1 by EGFR Activation Mediates the Immune Escape in EGFR-Driven NSCLC: Implication for Optional Immune Targeted Therapy for NSCLC Patients with EGFR Mutation

Abstract

Our results imply that EGFR-TKIs could not only directly inhibit tumor cell viability but also indirectly enhance antitumor immunity through the downregulation of PD-L1. Anti-PD-1/PD-L1 antibodies could be an optional therapy for EGFR-TKI sensitive patients, especially for EGFR-TKIs resistant NSCLC patients with EGFR mutation. Combination of EGFR-TKIs and anti-PD-1/PD-L1 antibodies treatment in NSCLC is not supported by the current study but warrant more studies to move into clinical practice.

Inhibition of yes‐associated protein down‐regulates PD‐L1 (CD274) expression in human malignant pleural mesothelioma

“…Two recent studies reported that the EGFR pathway is involved in the regulation of PD‐L1 expression in EGFR‐mutant human non‐small‐cell lung cancer (NSCLC) cells, whereby inhibition of EGFR signalling decreased PD‐L1 expression in some EGFR‐mutant NSCLC cells, suggesting that tumour PD‐L1 expression may be regulated by cancer‐driven mutation 27, 28. Five of the human MPM cell lines (H290, H2052, 211H, H28 and MS‐1) used in our study had a low p‐YAP (S127)/YAP ratio and high GTIIC reporter activity.…”

Management of Italian Patients With Advanced Non–Small-Cell Lung Cancer After Second-Line Treatment: Results of the Longitudinal Phase of the LIFE Observational Study

“…110 However, the combination of EGFR-TKI and PD-1/PD-L1 inhibitors is controversial on the basis of the current evidence and it is worthy to be more thoroughly investigated for the following reasons: (1) unexpected toxicity occurred in the TATTON trial; and (2) a controversial correlation between EGFR mutations and expression level of PD-L1. Previous studies showed that activating the EGFR plays a key role in remodeling the tumor environment by upregulating PD-L1, indicating that the expression of PD-L1 is driven by oncogene, 111,112 and EGFR-TKI downregulates PD-L1 expression, which is a potential predictive biomarker for PD-1/PD-L1 inhibitors. 112 Thus, combining EGFR-TKIs and PD-1/PD-L1 blockade seems to have similar but not synergistic effects on processes of combatting cancer.…”

“…Previous studies showed that activating the EGFR plays a key role in remodeling the tumor environment by upregulating PD-L1, indicating that the expression of PD-L1 is driven by oncogene, 111,112 and EGFR-TKI downregulates PD-L1 expression, which is a potential predictive biomarker for PD-1/PD-L1 inhibitors. 112 Thus, combining EGFR-TKIs and PD-1/PD-L1 blockade seems to have similar but not synergistic effects on processes of combatting cancer. However, one study pointed out that EGFR status was not associated with PD-L1 expression.…”

A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint

“…Recently, it was reported that EGFR activation by either EGF, exon-19 deletions or L858R mutation promotes PD-L1 expression by cancer cells. 6 , 23 EGFR overexpression is known to promote immune evasion of malignant cells by inhibiting the activation of signal transducer and activator of transcription 1 (STAT1) while promoting that of STAT3. 24 , 25 Several EGFR-targeted agents are currently available that inhibit oncogenic EGFR signaling, including small-molecule EGFR kinase inhibitors (gefitinib, erlotinib and osimertinib) and antagonistic antibodies (necitumumab, nimotuzumab and cetuximab).…”

“…2 Indeed, PD-L1 expression by cancer cells was found to be associated with unfavorable prognosis in various malignancies. 3-5 In this process, cancer cells constitutively express PD-L1 due to aberrant oncogenic signaling 6 or upregulate PD-L1 in response to IFN-γ locally released by activated anticancer T cells. 2 , 7 …”