Abstract
PurposeGalanin receptor 2 (GALR2) plays a significant role in the progression of head and neck squamous cell carcinomas (HNSCC). Since there is virtually no information on immunomodulation mediated by its ligand in the tumor microenvironment, we assessed the effects of galanin on peripheral blood mononuclear cells (PBMCs).MethodsAfter verification of GALR2 expression and it activity in PBMCs we evaluated the effect of galanin and conditioned media from HNSCC cell lines silenced for galanin or antibody-depleted, on proliferation, apoptosis, cytokine expression and activation/differentiation of immune cells.ResultsWe found that galanin alone and as a component of the HNSCC secretome decreased HNSCC cell proliferation and expression of pro-inflammatory cytokines (IFNγ, IL-12, IL-17A, IL-1α, IL-6 and TNF-α), whilst increasing apoptosis and expression of pro-tumoral cytokines/growth factors (IL-10, IL-4, PDGF and GM-CSF). T cell activation (using CD69 as activation marker) and anti-tumoral phenotypes in CD4+ T cells (Th1 and Th17) were found to be suppressed. In vivo, tumor growth was found to be increased in the presence of galanin-stimulated PBMCs. Data from The Cancer Genome Atlas (TCGA) revealed that high expression of galanin was associated with a reduced overall survival of patients with HNSCC.ConclusionOur data indicate that galanin secreted by HNSCC cells exhibits immune-suppressive and pro-tumoral effects.
Highlights
Galanin has been implicated in multiple physiological and pathological processes in the nervous system, the endocrine system, metabolism, energy homeostasis and bone [1, 2]
We evaluated the expression of spexin, which induces galanin receptor expression, in head and neck squamous cell carcinomas (HNSCC) cells, but its expression was very low compared with galanin and did not affect survival in The Cancer Genome Atlas (TCGA) datasets (Fig. S1)
The expression of galanin receptors by peripheral blood mononuclear cells (PBMCs) was verified by RT-qPCR and immunoblotting
Summary
Galanin has been implicated in multiple physiological and pathological processes in the nervous system, the endocrine system, metabolism, energy homeostasis and bone [1, 2]. Recent findings suggest a role for galanin in innate immunity, inflammation and cancer [1, 2]. Galanin induces three G protein coupled receptors: GALR1, GALR2 and GALR3 [3, 4]. GALR2 plays an important role in HNSCC [5–7] and stimulation of GALR2 activates RAP1, a small GTPase, that subsequently induces ERK, AKT and p38, leading to HNSCC cell proliferation, survival and the secretion of proangiogenic cytokines such as VEGF, respectively [5, 6]. GALR2 induces invasion of HNSCC cells via NFATC2-mediated transcription of cyclooxygenase-2, which enzymatically facilitates prostaglandin E2 production, thereby promoting tumor progression [7]. Another study showed that GALR2 promotes apoptosis in HNSCC cells [8]
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