Inhibition of MEK with trametinib enhances the efficacy of anti-PD-L1 inhibitor by regulating anti-tumor immunity in head and neck squamous cell carcinoma

Abstract

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-γ 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.

Tumor Membrane Vesicle Vaccine Augments the Efficacy of Anti-PD1 Antibody in Immune Checkpoint Inhibitor-Resistant Squamous Cell Carcinoma Models of Head and Neck Cancer

“…Blocking the interaction using anti-PD-1 antibody prevents negative signaling and enhances the anti-tumor T cell response. A recent study has shown that anti-PD-L1 antibody therapy failed to inhibit SCC VII tumor growth, but combination treatment with MEK inhibitor and anti-PD-L1 antibody showed a synergistic effect in inhibiting tumor growth [35]. Our study demonstrates that early administration of anti-PD-1 antibody treatment inhibits SCC VII tumor growth and induces a durable protective anti-tumor immunity, suggesting that SCC VII cells are immunogenic.…”

“…The SCC VII squamous cell carcinoma cell line is derived from the abdominal cavity of C3H mice [50][51][52], but widely used as a model for squamous cell carcinomas of head and neck cancer as it behaves similarly to human HNSCC [28,29,35,53]. In this study, we compared the efficacy of the TMV vaccine immunotherapy in SCC VII with recently available MOC models [7,31,33,37].…”

Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib

“…Enhanced MEK activity can cause abnormal activation in the RAS-RAF-MEK-ERK pathway, which has been reported to be responsible for the pathogenesis of inflammation and approximately 30% of all human malignancies [4,5]. Thus, MEK has been the target of various drug discoveries [6][7][8][9][10][11][12][13][14], and inhibition of MEK activity may be used to treat MEK pathway activation-driven cancers.…”

Effect of apigenin on whole transcriptome profile of TNFα‑activated MDA‑MB‑468 triple negative breast cancer cells

“…In this work, for example, we show that apigenin suppressed the TNFα mediated rise in a potent tumor suppressor: CXCL10. While previous studies consistently that CXCL10 is up-regulated in normal vs. tumor tissue (76,77) this particular protein acts as the major tumor suppressor, evoked by IFN-γ treatment and somehow plays a role in the re-expression of MHC-1, PD-L1, the infiltration of anti-tumoral CD4(+) and CD8(+) T cells (78,79), NK cells, cytotoxic lymphocytes (CTLs) to the tumor to turn on immune surveillance and heighted survival odds in diverse human cancers (80)(81)(82). While the beneficial effects of apigenin in cancer are consistently reported, any compound that would turn off the CXCL9, -10, -11/CXCR3 axis could harm the host immunes system to destroy self-malignant tumor tissue (83).…”