EGFR signaling suppresses type 1 cytokine-induced T-cell attracting chemokine secretion in head and neck cancer

Abstract

Resistance to antitumor immunity can be promoted by the oncogenic pathways operational in human cancers, including the epidermal growth factor receptor (EGFR) pathway. Here we studied if and how EGFR downstream signaling in head and neck squamous cell carcinoma (HNSCC) can affect the attraction of immune cells. HPV-negative and HPV-positive HNSCC cell lines were analyzed in vitro for CCL2, CCL5, CXCL9, CXCL10, IL-6 and IL-1β expression and the attraction of T cells under different conditions, including cetuximab treatment and stimulation with IFNγ and TNFα using qPCR, ELISA and migration experiments. Biochemical analyses with chemical inhibitors and siRNA transfection were used to pinpoint the underlying mechanisms. Stimulation of HNSCC cells with IFNγ and TNFα triggered the production of T-cell attracting chemokines and required c-RAF activation. Blocking of the EGFR with cetuximab during this stimulation increased chemokine production in vitro, and augmented the attraction of T cells. Mechanistically, cetuximab decreased the phosphorylation of MEK1, ERK1/2, AKT, mTOR, JNK, p38 and ERK5. Chemical inhibition of EGFR signaling showed a consistent and pronounced chemokine production with MEK1/2 inhibitor PD98059 and JNK inhibitor SP600125, but not with inhibitors of p38, PI3K or mTOR. Combination treatment with cetuximab and a MEK1/2 or JNK inhibitor induced the highest chemokine expression. In conclusion, overexpression of EGFR results in the activation of multiple downstream signaling pathways that act simultaneously to suppress type 1 cytokine stimulated production of chemokines required to amplify the attraction of T cells.

Tumor-targeting anti-EGFR x anti-PD1 bispecific antibody inhibits EGFR-overexpressing tumor growth by combining EGFR blockade and immune activation with direct tumor cell killing

“…There are in theory several rationales for co-targeting EGFR on tumor cells and PD1 on T cells via a BsAb: 1) accumulating evidence demonstrated that stimulation of EGFR signaling can suppress immune responses and enhance the tumor cell evasion of immune surveillance, including induction of PDL-1 overexpression on the surface of tumor cells, stimulation of VEGF, IL6, IL10 secretion, activation of regulatory T cells (Tregs) and downregulation of T cell chemokines [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] . Inhibition of EGFR signaling in tumor cells, therefore, not only can exert direct antitumor activity but also may create a more favorable anti-tumor immune microenvironment [40 , 46] ; 2) By targeting EGFR-overexpressing tumor cells, anti-PD1 x EGFR BsAb may enhance the antibody localization to specifically target and activate T cells and other immune cells within the tumor microenvironment [29] ; 3) the BsAb simultaneously targeting EGFR on tumor cell surface and PD1 on T cells may likely be able to create direct cell-cell interaction/engagement of the tumor cells and the immune cells, and leads to the formation of immunological synapse, resulting in CD8 + T cell activation and potent tumor cell killing [30 , 47] .…”

Combination of β2-AR Blocker and COX-2 Inhibitor Suppresses Development of Oral Squamous Cell Carcinoma

“…EGFR can promote tumor cell proliferation, metastasis, anti-apoptosis and angiogenesis by activating its downstream signaling pathways Ras/Raf/MEK/ERK and phosphatidylinositide 3-kinases/protein kinase B (PI3K/Akt) [45,46]. Some studies reported that EGFR also could promote the tumor immune escape mechanism [47,48]. In recent years, EGFR-targeted therapy has been used to clinical treatment of OSCC [49][50][51][52].…”

Mitochondrial Dysfunction Pathway Networks and Mitochondrial Dynamics in the Pathogenesis of Pituitary Adenomas

“…A study found a number of tumor immunity-related inflammatory cells, for example, cytotoxic T cells (CTLs), regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and natural killer (NK) cells (37). It also found a number of tumor immunity-related pathways, such as altered interleukin signaling (117), MHC-I pathway (118), type 1 cytokine-induced T-cell (119), interferon gamma signaling (120), type I interferon-mediated responses (121), and transcription factor nuclear factor-kappa B (122). Along with the advancement in tumor immunology, the immune-checkpoint blockade therapy has been an important aspect in the mode of combined therapy of tumor.…”