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

// Koung Jin Suh 1, 3, * , Ji Hea Sung 1, * , Jin Won Kim 1 , Song-Hee Han 2 , Hye Seung Lee 2 , Ahrum Min 4 , Mi Hyun Kang 1 , Ji Eun Kim 1 , Ji-Won Kim 1 , Se Hyun Kim 1 , Jeong-Ok Lee 1 , Yu Jung Kim 1 , Keun-Wook Lee 1 , Jee Hyun Kim 1 , Soo-Mee Bang 1 , Seock-Ah Im 3, 4 and Jong Seok Lee 1 1 Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Bundang-gu, Seongnam, Korea 2 Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Bundang-gu, Seongnam, Korea 3 Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Jongno-gu, Seoul, Korea 4 Cancer Research Institute, Seoul National University, Jongno-gu, Seoul, Korea * These authors have contributed equally to this work Correspondance to: Jin Won Kim, email: jwkim@snubh.org Keywords: PD-L1, cytokine, EGFR, HER2, PI3K Received: January 04, 2017      Accepted: June 11, 2017      Published: July 12, 2017 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.