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Oncotarget. 2017 Jul 12;8(38):63901-63910. doi: 10.18632/oncotarget.19194. eCollection 2017 Sep 8.

EGFR or HER2 inhibition modulates the tumor microenvironment by suppression of PD-L1 and cytokines release.

Author information

1
Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Bundang-gu, Seongnam, Korea.
2
Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Jongno-gu, Seoul, Korea.
3
Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Bundang-gu, Seongnam, Korea.
4
Cancer Research Institute, Seoul National University, Jongno-gu, Seoul, Korea.
#
Contributed equally

Abstract

BACKGROUND:

Characteristics of tumor microenvironment have been suggested as predictive markers of anti-EGFR or anti-HER2 treatment response. However, the effect of EGFR/HER2 signal blockade on the tumor immune microenvironment is unclear.

METHODS:

EGFR/HER2 pathway signaling and PD-L1 expression in gastric cancer cell lines were screened by western blot analysis. PD-L1 and HER2 expressions in 251 resected gastric tumors were determined by immunohistochemistry, and changes in EFGR, HER2, and PD-L1 expression in paired specimens between pre- and post-chemotherapy were evaluated. PD-L1 expression in HER2-amplified cell lines was evaluated by western blotting, fluorescence-activated cell sorting, reverse transcription, and real-time quantitative PCR analyses before and after afatinib, lapatinib, pictilisib and trametinib treatment. Changes in cytokines were evaluated by reverse transcription, real-time quantitative PCR, and enzyme-linked immunosorbent assay after EGFR/HER2 inhibition.

RESULTS:

Cell lines with pEGFR or pHER2 overexpression showed higher PD-L1 expression. In resected gastric tumors, HER2 expression was significantly associated with PD-L1 expression (p=0.030). PD-L1 overexpression accompanied by increased HER2 expression was identified in a post-chemotherapy specimen from a patient with an initial HER2/PD-L1-negative tumor. In HER2-overexpressing cell lines, PD-L1 expression was decreased in a dose- and time-dependent manner after afatinib and lapatinib treatment. PI3K pathway inhibition by pictilisib, but not MEK pathway inhibition by trametinib, resulted in PD-L1 suppression. After lapatinib treatment, the release of CCL2, CCL21, VEGF and CXCL1 decreased in a dose-dependent manner.

CONCLUSIONS:

Inhibition of the EGFR/HER2 signaling pathway, particularly of downstream PI3K activity, suppressed PD-L1 and release of cytokines, suggesting that EGFR/HER2 inhibition may create a more favorable milieu for tumor immunotherapy.

KEYWORDS:

EGFR; HER2; PD-L1; PI3K; cytokine

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