EGFR or HER2 inhibition modulates the tumor microenvironment by suppression of PD-L1 and cytokines release
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Koung Jin Suh1,3,*, Ji Hea Sung1,*, Jin Won Kim1, Song-Hee Han2, Hye Seung Lee2, Ahrum Min4, Mi Hyun Kang1, Ji Eun Kim1, Ji-Won Kim1, Se Hyun Kim1, Jeong-Ok Lee1, Yu Jung Kim1, Keun-Wook Lee1, Jee Hyun Kim1, Soo-Mee Bang1, Seock-Ah Im3,4 and Jong Seok Lee1
1Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Bundang-gu, Seongnam, Korea
2Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Bundang-gu, Seongnam, Korea
3Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Jongno-gu, Seoul, Korea
4Cancer Research Institute, Seoul National University, Jongno-gu, Seoul, Korea
*These authors have contributed equally to this work
Jin Won Kim, email: [email protected]
Keywords: PD-L1, cytokine, EGFR, HER2, PI3K
Received: January 04, 2017 Accepted: June 11, 2017 Published: July 12, 2017
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.
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