Chronic Stress Exacerbates the Immunosuppressive Microenvironment and Progression of Gliomas by Reducing Secretion of CCL3.

As understanding of cancer has deepened, increasing attention has been turned to the roles of psychological factors, especially chronic stress-induced depression, in the occurrence and development of tumors. However, whether and how depression affects the progression of gliomas are still unclear. In this study, we have revealed that chronic stress inhibited the recruitment of tumor-associated macrophages (TAM) and other immune cells, especially M1-type TAMs and CD8+ T cells, and decreased the level of proinflammatory cytokines in gliomas, leading to an immunosuppressive microenvironment and glioma progression. Mechanistically, by promoting the secretion of stress hormones, chronic stress inhibited the secretion of the chemokine CCL3 and the recruitment of M1-type TAMs in gliomas. Intratumoral administration of CCL3 reprogrammed the immune microenvironment of gliomas and abolished the progression of gliomas induced by chronic stress. Moreover, levels of CCL3 and M1-type TAMs were decreased in the tumor tissues of glioma patients with depression, and CCL3 administration enhanced the antitumor effect of anti-PD-1 therapy in orthotopic models of gliomas undergoing chronic stress. In conclusion, our study has revealed that chronic stress exacerbates the immunosuppressive microenvironment and progression of gliomas by reducing the secretion of CCL3. CCL3 alone or in combination with an anti-PD-1 may be an effective immunotherapy for the treatment of gliomas with depression. See related Spotlight by Cui and Kang, p. 514.

A Trojan-Horse-Like Biomimetic Nano-NK to Elicit an Immunostimulatory Tumor Microenvironment for Enhanced GBM Chemo-Immunotherapy.

Although the chemo- and immuno-therapies have obtained good responses for several solid tumors, including those with brain metastasis, their clinical efficacy in glioblastoma (GBM) is disappointing. The lack of safe and effective delivery systems across the blood-brain barrier (BBB) and the immunosuppressive tumor microenvironment (TME) are two main hurdles for GBM therapy. Herein, a Trojan-horse-like nanoparticle system is designed, which encapsulates biocompatible PLGA-coated temozolomide (TMZ) and IL-15 nanoparticles (NPs) with cRGD-decorated NK cell membrane (R-NKm@NP), to elicit the immunostimulatory TME for GBM chemo-immunotherapy. Taking advantage of the outer NK cell membrane cooperating with cRGD, the R-NKm@NPs effectively traversed across the BBB and targeted GBM. In addition, the R-NKm@NPs exhibited good antitumor ability and prolonged the median survival of GBM-bearing mice. Notably, after R-NKm@NPs treatment, the locally released TMZ and IL-15 synergistically stimulated the proliferation and activation of NK cells, leading to the maturation of dendritic cells and infiltration of CD8+ cytotoxic T cells, eliciting an immunostimulatory TME. Lastly, the R-NKm@NPs not only effectively prolonged the metabolic cycling time of the drugs in vivo, but also has no noticeable side effects. This study may offer valuable insights for developing biomimetic nanoparticles to potentiate GBM chemo- and immuno-therapies in the future.

Chronic stress accelerates glioblastoma progression via DRD2/ERK/ß-catenin axis and Dopamine/ERK/TH positive feedback loop.

BACKGROUND: After diagnosis, glioblastoma (GBM) patients undertake tremendous psychological problems such as anxiety and depression, which may contribute to GBM progression. However, systematic study about the relationship between depression and GBM progression is still lacking. METHODS: Chronic unpredictable mild stress and chronic restrain stress were used to mimic human depression in mice. Human GBM cells and intracranial GBM model were used to assess the effects of chronic stress on GBM growth. Targeted neurotransmitter sequencing, RNA-seq, immunoblotting and immunohistochemistry were used to detect the related molecular mechanism. RESULTS: Chronic stress promoted GBM progression and up-regulated the level of dopamine (DA) and its receptor type 2 (DRD2) in tumor tissues. Down-regulation or inhibition of DRD2 abolished the promoting effect of chronic stress on GBM progression. Mechanistically, the elevated DA and DRD2 activated ERK1/2 and consequently inhibited GSK3ß activity, leading to ß-catenin activation. Meanwhile, the activated ERK1/2 up-regulated tyrosine hydroxylase (TH) level in GBM cells and then promoted DA secretion, forming an autocrine positive feedback loop. Remarkably, patients with high-depression exhibited high DRD2 and ß-catenin levels, which showed poor prognosis. Additionally, DRD2 specific inhibitor pimozide combined with temozolomide synergistically inhibited GBM growth. CONCLUSIONS: Our study revealed that chronic stress accelerates GBM progression via DRD2/ERK/ß-catenin axis and Dopamine/ERK/TH positive feedback loop. DRD2 together with ß-catenin may serve as a potential predictive biomarker for worse prognosis as well as therapeutic target of GBM patients with depression.

SU4312 Represses Glioma Progression by Inhibiting YAP and Inducing Sensitization to the Effect of Temozolomide.

SU4312, initially designed as a multi-target tyrosine kinase inhibitor, is consequently reported to inhibit tumor angiogenesis by blocking VEGFR. However, although SU4312 can penetrate the brain-blood barrier, its potential to inhibit glioma growth is unknown. In this study, we report that SU4312 inhibited glioma cell proliferation and down-regulated yes-associated protein (YAP), the key effector of the hippo pathway. The exogenous over-expression of YAP partially restored the inhibitory effect of SU4312 on glioma progression. Interestingly, SU4312 sensitized the antitumor effect of temozolomide, both in vitro and in vivo. Moreover, SU4312 decreased the M2tumor-associated macrophages and enhanced anti-tumor immunity by down-regulating the YAP-CCL2 axis. In conclusion, our results suggest that SU4312 represses glioma progression by down-regulating YAP transcription and consequently CCL2 secretion. SU4312 may be synergistic with temozolomide for glioma treatment.