A Novel PD-L1-Containing MSLN Targeting Vaccine for Lung Cancer Immunotherapy.

Therapeutic tumor vaccines have become an important breakthrough in the treatment of various solid tumors including lung cancer. Dendritic cells (DCs)-based tumor vaccines targeting tumor-associated antigens (TAAs) play a key role in immunotherapy and immunoprevention. However, the weak immunogenicity of TAAs and low immune response rates are a major challenge faced in the application of therapeutic tumor vaccines. Here, we tested whether targeting an attractive target Mesothelin (MSLN) and PD-L1 immune checkpoint molecule to DCs in vivo would elicit therapeutic antitumor cytotoxic T lymphocyte (CTL) response. We generated specific MSLN fragment combined with PD-L1 and GM-CSF peptide immunogen (MSLN-PDL1-GMCSF) based on the novel anti-PD-L1 vaccination strategy we recently developed for the cancer treatment and prevention. We found that DCs loaded with MSLN-PDL1-GMCSF vaccine elicited much stronger endogenous anti-PD-L1 antibody and T cell responses in immunized mice and that antigen specific CTLs had cytolytic activities against tumor cells expressing both MSLN and PD-L1. We demonstrated that vaccination with MSLN-PDL1-GMCSF potently inhibited the tumor growth of MSLN+ and PD-L1+ lung cancer cells, exhibiting a significant therapeutic anti-tumor potential. Furthermore, PD-1 blockade further improved the synergistic antitumor therapeutic efficacy of MSLN-PDL1-GMCSF vaccine in immunized mice. In summary, our data demonstrated for the first time that this PD-L1-containing MSLN therapeutic vaccine can induce persistent anti-PD-L1 antibody and CTL responses, providing an effective immunotherapeutic strategy for lung cancer immunotherapy by combining MSLN-PDL1-GMCSF vaccine and PD-1 blockade.

A Novel Therapeutic Tumor Vaccine Targeting MUC1 in Combination with PD-L1 Elicits Specific Anti-Tumor Immunity in Mice.

Dendritic cells (DCs), as professional antigen-presenting cells (APCs), play a key role in the initiation and regulation of humoral and cellular immunity. DC vaccines loaded with different tumor-associated antigens (TAAs) have been widely used to study their therapeutic effects on cancer. A number of clinical trials have shown that DCs are safe as an antitumor vaccine and can activate certain anti-tumor immune responses; however, the overall clinical efficacy of DC vaccine is not satisfactory, so its efficacy needs to be enhanced. MUC1 is a TAA with great potential, and the immune checkpoint PD-L1 also has great potential for tumor treatment. Both of them are highly expressed on the surface of various tumors. In this study, we generated a novel therapeutic MUC1-Vax tumor vaccine based on the method of PD-L1-Vax vaccine we recently developed; this novel PD-L1-containing MUC1-Vax vaccine demonstrated an elevated persistent anti-PD-L1 antibody production and elicited a much stronger protective cytotoxic T lymphocyte (CTL) response in immunized mice. Furthermore, the MUC1-Vax vaccine exhibited a significant therapeutic anti-tumor effect, which significantly inhibited tumor growth by expressing a high MUC1+ and PD-L1+ level of LLC and Panc02 tumor cells, and prolonged the survival of cancer-bearing animals. Taken together, our study provides a new immunotherapy strategy for improving the cross-presentation ability of therapeutic vaccine, which may be applicable to pancreatic cancer, lung cancer and for targeting other types of solid tumors that highly express MUC1 and PD-L1.

[Changes in selectin in early stage of lung injury induced by endotoxic shock in macaque].

OBJECTIVE: To investigate the change in selectin and its effect on lung injury induced by endotoxic [lipopolysaccharide (LPS)] shock in macaque. METHODS: Eleven macaques were randomly divided into two groups: control group (n=5) and LPS group (n=6). The animals of the control group received injection of 1 ml/kg normal saline, and the animals of the LPS group received a dose of 2.8 mg/kg LPS intravenously. The plasma contents of P-selectin and L-selectin were assayed before LPS challenge, 60 and 120 minutes after LPS challenge. Ultrastructure of lung tissue and immunohistochemical assay of P-selectin and L-selectin in the lung were observed. RESULTS: Administration of LPS did not changed P-selectin level in plasma, but decreased the L-selectin level at 120 minutes after LPS challenge in both groups (all P<0.05). By immunohistochemical staining, P-selectin and L-selectin were identified on endothelial cells of alveolar wall of LPS animals, whereas no positive staining of P-selectin and L-selectin was showed in control animals. Damages to alveolar type I and II cells, slight transudation of red blood corpuscles, and damage to the basement membrane were observed with electron microscopy in the endotoxin challenged macaques. No pathological changes were observed in the control group. CONCLUSION: Administration of LPS induces expression of P-selectin and L-selectin in alveolar wall and causes alveolar damages in early-phase of endotoxic shock. In the meantime, the L-selectin and P-selectin in plasma do not change. The selectins play an important role in the pathogenesis of lung injury in the early-phase of endotoxic shock.