RGS16 regulated by let-7c-5p promotes glioma progression by activating PI3K-AKT pathway

Gliomas are the most common central nervous system tumours;they are highly aggressive and have a poor prognosis. RGS16 belongs to the regulator of G-protein signalling (RGS) protein family, which plays an important role in promoting various cancers, such as breast cancer, pancreatic cancer, and colorectal cancer. Moreover, previous studies confirmed that let-7c-5p, a well-known microRNA, can act as a tumour suppressor to regulate the progression of various tumours by inhibiting the expression of its target genes. However, whether RGS16 can promote the progression of glioma and whether it is regulated by miR let-7c-5p are still unknown. Here, we confirmed that RGS16 is upregulated in glioma tissues and that high expression of RGS16 is associated with poor survival. Ectopic deletion of RGS16 significantly suppressed glioma cell proliferation and migration both in vitro and in vivo. Moreover, RGS16 was validated as a direct target gene of miR let-7c-5p. The overexpression of miR let-7c-5p obviously downregulated the expression of RGS16, and knocking down miR let-7c-5p had the opposite effect. Thus, we suggest that the suppression of RGS16 by miR let-7c-5p can promote glioma progression and may serve as a potential prognostic biomarker and therapeutic target in glioma.

Anti-PD-L1/TGF-BR fusion protein (SHR-1701) overcomes disrupted lymphocyte recovery-induced resistance to PD-1/PD-L1 inhibitors in lung cancer

Background:Second-generation programmed cell death-protein 1/pro-grammed death-ligand 1(PD-1/PD-L1)inhibitors,such as bintrafusp alfa(M7824),SHR-1701,and YM101,have been developed to simultaneously block PD-1/PD-L1 and transforming growth factor-beta/transforming growth factor-beta receptor(TGF-P/TGF-βR).Consequently,it is necessary to identify predictive factors of lung cancer patients who are not only resistant to PD-1/PD-LI inhibitors but also sensitive to bifunctional drugs.The purpose of this study was to search for such predictors.Methods:Multivariable Cox regression was used to study the association between the clinical outcome of treatment with PD-1/PD-L1 inhibitors and lym-phocyte recovery after lymphopenia in lung cancer patients.Murine CMT167 lung cancer cells were engineered to express the firefly luciferase gene and implanted orthotopically in the lung of syngeneic mice.Bioluminescence imag-ing,flow cytometry,and immunohistochemistry were employed to detrmine response to immunotherapy and function of tumor-infiltrating immune cells.Results:For lung cancer patients treated with anti-PD-1/PD-LI antibodies,poor lymphocyte recovery was associated with a shorter progression-free survival(PFS;P<0.001),an accumulation of regulatory T cells(Tregs),and an elimi-nation of CD8+T cells in the peripheral blood.Levels of CD8+T cells and Treg cells were also imbalanced in the tumors and peripheral immune organs of mice with poor lymphocyte recovery after chemotherapy.Moreover,these mice failed to respond to anti-PD-1 antibodies but remained sensitive to the anti-PD-LI/TGF-βR fusion protein(SHR-1701).Consistently,SHR-1701 but not anti-PD-1 antibod-ies,markedly enhanced IFN-γproduction and Ki-67 expression in peripheral CD8+T cells from patients with impaired lymphocyte recovery.Conclusions:Lung cancer patients with poor lymphocyte recovery and suffer-ing from persistent lymphopenia after previous chemotherapy are resistant to anti-PD-1/PD-L1 antibodies but might be sensitive to second-generation agents such as SHR-1701.