Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors

Abstract

The success in lung cancer therapy with Programmed Death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between Epidermal Growth Factor Receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, cytotoxic T lymphocyte antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased cytotoxic T cells and increased markers of T cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape, and mechanistically link treatment response to PD-1 inhibition.

Clinicopathologic analysis of programmed cell death-1 and programmed cell death-ligand 1 and 2 expressions in pulmonary adenocarcinoma: comparison with histology and driver oncogenic alteration status

“…This was comparable to previous in vitro studies demonstrating that EGFR pathway activation triggered upregulation of PD-L1 in lung cancer cells in an EGFR mutation-independent manner, and that PD-L1 (CD274) mRNA levels were not statistically different between lung cancer cell lines harboring and lacking EGFR mutation. 15 Meanwhile, a strong positive correlation between EGFR with PD-L1 expression observed in this study hints that the EGFR pathway might contribute to the upregulation of PD-L1 in pulmonary adenocarcinomas. Of note, patients with ALK translocation tended to show high expression of both PD-L1 and PD-L2 in pulmonary adenocarcinomas.…”

“…15,37 However, it has also been reported that PD-L1 expression was not associated with EGFR, KRAS, or BRAF mutation or ALK translocation. 20 In contrast, other studies reported that PD-L1 overexpression was associated with EGFR mutation in non-small-cell lung cancer.…”

“…6,8,13 Furthermore, PD-1 + T cells were observed in tumor tissues and were functionally impaired upon engagement by PD-L1 or PD-L2. [14][15][16] As with CTLA-4, blockade of the PD-1/PD-L pathway enhanced antitumor immune responses by restoring T-cell functions. 11 Consistently, blockade of PD-1 or PD-L1 controlled the progression of various cancers and prolonged the survival of advanced pulmonary adenocarcinoma patients in clinical trials.…”

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).…”

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.…”