Emerging phagocytosis checkpoints in cancer immunotherapy

Cancer immunotherapy,mainly including immune checkpoints-targeted therapy and the adoptive transfer of engineered immune cells,has revolutionized the oncology landscape as it utilizes patients’own immune systems in combating the cancer cells.Cancer cells escape immune surveillance by hijacking the corresponding inhibitory pathways via overexpressing checkpoint genes.Phagocytosis checkpoints,such as CD47,CD24,MHC-I,PD-L1,STC-1 and GD2,have emerged as essential checkpoints for cancer immunotherapy by functioning as“don’t eat me”signals or interacting with“eat me”signals to suppress immune responses.Phagocytosis checkpoints link innate immunity and adaptive immunity in cancer immunotherapy.Genetic ablation of these phagocytosis checkpoints,as well as blockade of their signaling pathways,robustly augments phagocytosis and reduces tumor size.Among all phagocytosis checkpoints,CD47 is the most thoroughly studied and has emerged as a rising star among targets for cancer treatment.CD47-targeting antibodies and inhibitors have been investigated in various preclinical and clinical trials.However,anemia and thrombocytopenia appear to be formidable challenges since CD47 is ubiquitously expressed on erythrocytes.Here,we review the reported phagocytosis checkpoints by discussing their mechanisms and functions in cancer immunotherapy,highlight clinical progress in targeting these checkpoints and discuss challenges and potential solutions to smooth the way for combination immunotherapeutic strategies that involve both innate and adaptive immune responses.

FOXO1-miR-506 axis promotes chemosensitivity to temozolomide and suppresses invasiveness in glioblastoma through a feedback loop of FOXO1/miR-506/ETS1/FOXO1

To explore the role of forkhead box protein O1(FOXO1)in the progression of glioblastoma multiforme(GBM)and related drug resistance,we deciphered the roles of FOXO1 and miR-506 in proliferation,apoptosis,migration,invasion,autophagy,and temozolomide(TMZ)sensitivity in the U251 cell line using in vitro and in vivo experiments.Cell viability was tested by a cell counting kit-8(CCK8)kit;migration and invasion were checked by the scratching assay;apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling(TUNEL)staining and flow cytometry.The construction of plasmids and dual-luciferase reporter experiment were carried out to find the interaction site between FOXO1 and miR-506.Immunohistochemistry was done to check the protein level in tumors after the in vivo experiment.We found that the FOXO1-miR-506 axis suppresses GBM cell invasion and migration and promotes GBM chemosensitivity to TMZ,which was mediated by autophagy.FOXO1 upregulates miR-506 by binding to its promoter to enhance transcriptional activation.MiR-506 could downregulate E26 transformation-specific 1(ETS1)expression by targeting its 3'-untranslated region(UTR).Interestingly,ETS1 promoted FOXO1 translocation from the nucleus to the cytosol and further suppressed the FOXO1-miR-506 axis in GBM cells.Consistently,both miR-506 inhibition and ETS1 overexpression could rescue FOXO1 overactivation-mediated TMZ chemosensitivity in mouse models.Our study demonstrated a negative feedback loop of FOXO1/miR-506/ETS1/FOXO1 in GBM in regulating invasiveness and chemosensitivity.Thus,the above axis might be a promising therapeutic target for GBM.

Baicalein inhibits SARS-CoV-2/VSV replication with interfering mitochondrial oxidative phosphorylation in a mPTP dependent manner

Dear Editor,The ongoing outbreak of pneumonia(coronavirus disease 2019,COVID-19)caused by severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)has become a global health emergency.Scutellaria Baicalensis Georgi extract,a Traditional Chinese Medicine(TCM)widely used for treating infection of multiple different viruses,1 also shows beneficial effects when treating COVID-19.However,underline mechanism for broad antiviral activity of Scutellaria B.extract remains elusive,which limits its further application.