Dysfunction of dendritic cells in tumor microenvironment and immunotherapy

Dendritic cells(DCs)comprise diverse cell populations that play critical roles in antigen presentation and triggering immune responses in the body.However,several factors impair the immune function of DCs and may promote immune evasion in cancer.Understanding the mechanism of DC dysfunction and the diverse functions of heterogeneous DCs in the tumormicroenvironment(TME)is critical for designing effective strategies for cancer immunotherapy.Clinical applications targeting DCs summarized in this report aim to improve immune infiltration and enhance the biological function of DCs to modulate the TME to prevent cancer cells from evading the immune system.Herein,factors in the TME that induce DC dysfunction,such as cytokines,hypoxic environment,tumor exosomes and metabolites,and co-inhibitory molecules,have been described.Furthermore,several key signaling pathways involved in DC dysfunction and signal-relevant drugs evaluated in clinical trials were identified.Finally,this review provides an overview of current clinical immunotherapies targeting DCs,especially therapies with proven clinical outcomes,and explores future developments in DC immunotherapies.

Neutralization of SARS-CoV-2 infection by antibodies targeting diverse epitopes

The CoVID-19 pandemic that started in late 2019 is sweeping through the world,posing historic challenges to global health,and disrupting social and economic lives.Previous and recent studies indicate that monoclonal antibodies can be efficacious in preventing and treating SARSCoV-1 and SARS-CoV-2 infections.Using a phage display platform,we have identified dozens of monoclonal antibodies that bind to diverse epitope groups on the SARS-CoV-2 spike protein.Many of them bound to the receptor binding domain(RBD)and inhibited ACE2-RBD interaction.

Mutational escape prevention by combination of four neutralizing antibodies that target RBD conserved regions and stem helix

New variants of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) appear rapidly every few months.They have showed powerful adaptive ability to circumvent the immune system. To further understand SARS-CoV-2’s adaptability so as to seek for strategies to mitigate the emergence of new variants, herein we investigated the viral adaptation in the presence of broadly neutralizing antibodies and their combinations. First, we selected four broadly neutralizing antibodies, including pan-sarbecovirus and pan-betacoronavirus neutralizing antibodies that recognize distinct conserved regions on receptor-binding domain(RBD) or conserved stem-helix region on S2 subunit.Through binding competition analysis, we demonstrated that they were capable of simultaneously binding.Thereafter, a replication-competent vesicular stomatitis virus pseudotyped with SARS-CoV-2 spike protein was employed to study the viral adaptation. Twenty consecutive passages of the virus under the selective pressure of individual antibodies or their combinations were performed. It was found that it was not hard for the virus to adapt to broadly neutralizing antibodies, even for pan-sarbecovirus and pan-betacoronavirus antibodies. The virus was more and more difficult to escape the combinations of two/three/four antibodies. In addition, mutations in the viral population revealed by high-throughput sequencing showed that under the selective pressure of three/four combinational antibodies, viral mutations were not prone to present in the highly conserved region across betacoronaviruses(stem-helix region), while this was not true under the selective pressure of single/two antibodies.Importantly, combining neutralizing antibodies targeting RBD conserved regions and stem helix synergistically prevented the emergence of escape mutations. These studies will guide future vaccine and therapeutic development efforts and provide a rationale for the design of RBD-stem helix tandem vaccine, which may help to impede the generation of novel variants.