Journal
ONCOIMMUNOLOGY
Volume 8, Issue 1, Pages -Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2018.1515057
Keywords
Head and neck squamous cell carcinoma; MEK inhibitor; anti-PD-1/PD-L1 mAb; immune recognition; immune infiltration
Categories
Funding
- Korea Health Technology R&D Project Strategic Center of Cell and Bio Therapy for Heart, Diabetes & Cancer through the Korea Health Industry Development Institute (KHIDI) [HI17C2085]
- National R&D Program for Cancer Control - Ministry of Health & Welfare (MHW), Republic of Korea [1420140]
- Korea Health Promotion Institute [1420140] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Major histocompatibility complex (MHC) class I downregulation is the primary immune evasion mechanism associated with failure in anti-PD-1/PD-L1 blockade therapies for cancer. Here, we examined the role of MEK signaling pathway inhibition in head and neck squamous cell carcinoma (HNSCC) both in vitro and in vivo. We found that trametinib, a small molecule inhibitor of MEK, significantly enhanced MHC class I and PD-L1 expression in human HNSCC cell lines, and this occurred via STAT3 activation. Trametinib also further upregulated the increase in CXCL9 and CXCL10 expression caused by IFN-gamma in HNSCC cells, which is associated with T cell infiltration in tumor tissues. Finally, we evaluated the therapeutic efficacy of trametinib combined with an anti-PD-L1 monoclonal antibody in vivo, using SCCVII mouse syngeneic tumor model for HNSCC. While neither PD-L1 blockade nor trametinib treatment alone affected tumor growth, the combined therapy significantly delayed tumor growth. Our results indicate that in the combined therapy trametinib increases CD8(+) T cell infiltration in the tumor site and upregulates antigen presentation, and this may be associated with enhanced PD-L1 blockade efficacy. Furthermore, our results suggest that this combination would therapeutically benefit patients with HNSCC.
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