Flt3 ligand augments immune responses to soluble PD1-based DNA vaccine via expansion of type 1 conventional DCs.

DNA vaccines are prospective for their efficient manufacturing process, but their immunogenicity is limited as they cannot efficiently induce CD8+ T cell responses. A promising approach is to induce cross-presentation by targeting antigens to DCs. Flt3L can expand the number of type 1 conventional DCs and thereby improve cross-presentation. In this study, we first constructed a DNA vaccine expressing soluble PD1 and found that the therapeutic effect of targeting DCs with only the sPD1 vaccine was limited. When combined the vaccine with Flt3L, the anti-tumor effect was significantly enhanced. Considering the complexity of tumors and that a single method may not be able to activate a large number of effective CD8+ T cells, we combined different drugs and the vaccine with Flt3L based on the characteristics of different tumors. In 4T1 model, we reduced Tregs through cyclophosphamide. In Panc02 model, we increased activated DCs by using aCD40. Both strategies triggered strong CD8+ T cell responses and significantly improved the therapeutic effect. Our study provides important support for the clinical exploration of DC-targeted DNA vaccines in combination with Flt3L.

Electroacupuncture stimulation modulates functional brain connectivity in the treatment of pediatric cerebral palsy: a case report.

Background: Pediatric cerebral palsy (CP) is a non-progressive brain injury syndrome characterized by central motor dysfunction and insufficient brain coordination ability. The etiology of CP is complex and often accompanied by diverse complications such as intellectual disability and language disorders, making clinical treatment difficult. Despite the availability of pharmacological interventions, rehabilitation programs, and spasticity relief surgery as treatment options for CP, their effectiveness is still constrained. Electroacupuncture (EA) stimulation has demonstrated great improvements in motor function, but its comprehensive, objective therapeutic effects on pediatric CP remain to be clarified. Methods: We present a case of a 5-year-old Chinese female child who was diagnosed with CP at the age of 4. The patient exhibited severe impairments in motor, language, social, and cognitive functions. We performed a 3-month period of EA rehabilitation, obtaining resting state functional magnetic resonance imaging (rs-fMRI) of the patient at 0 month, 3 months and 5 months since treatment started, then characterized brain functional connectivity patterns in each phase for comparison. Results: After a 12-month follow-up, notable advancements were observed in the patient's language and social symptoms. Changes of functional connectivity patterns confirmed this therapeutic effect and showed specific benefits for different recovery phase: starting from language functions then modulating social participation and other developmental behaviors. Conclusion: This is a pioneering report demonstrating the longitudinal effect of EA stimulation on functional brain connectivity in CP patients, suggesting EA an effective intervention for developmental disabilities (especially language and social dysfunctions) associated with pediatric CP.

The XCL1-Mediated DNA Vaccine Targeting Type 1 Conventional Dendritic Cells Combined with Gemcitabine and Anti-PD1 Antibody Induces Potent Antitumor Immunity in a Mouse Lung Cancer Model.

With the advent of cancer immunotherapy, there is a growing interest in vaccine development as a means to activate the cellular immune system against cancer. Despite the promise of DNA vaccines in this regard, their effectiveness is hindered by poor immunogenicity, leading to modest therapeutic outcomes across various cancers. The role of Type 1 conventional dendritic cells (cDC1), capable of cross-presenting vaccine antigens to activate CD8+T cells, emerges as crucial for the antitumor function of DNA vaccines. To address the limitations of DNA vaccines, a promising approach involves targeting antigens to cDC1 through the fusion of XCL1, a ligand specific to the receptor XCR1 on the surface of cDC1. Here, female C57BL/6 mice were selected for tumor inoculation and immunotherapy. Additionally, recognizing the complexity of cancer, this study explored the use of combination therapies, particularly the combination of cDC1-targeted DNA vaccine with the chemotherapy drug Gemcitabine (Gem) and the anti-PD1 antibody in a mouse lung cancer model. The study's findings indicate that fusion antigens with XCL1 effectively enhance both the immunogenicity and antitumor effects of DNA vaccines. Moreover, the combination of the cDC1-targeted DNA vaccine with Gemcitabine and anti-PD1 antibody in the mouse lung cancer model demonstrates an improved antitumor effect, leading to the prolonged survival of mice. In conclusion, this research provides important support for the clinical investigation of cDC1-targeting DNA vaccines in combination with other therapies.

Metformin improved a heterologous prime-boost of dual-targeting cancer vaccines to inhibit tumor growth in a melanoma mouse model.

Therapeutic cancer vaccines, which induce anti-tumor immunity by targeting specific antigens, constitute a promising approach to cancer therapy. Our previous work proposed an optimized heterologous immunization strategy using cancer gene vaccines co-targeting MUC1 and survivin. Administration of a DNA vaccine three times within a week followed by a single recombinant MVA (rMVA) boost was able to efficiently induce anti-tumor immunity and inhibit tumor growth in tumor-bearing mouse models However, the complex immunosuppressive tumor microenvironment always limits infiltration by vaccine-induced T cells. Modifying the immunosuppressive microenvironment of tumors would be a breakthrough in enhancing the therapeutic effects of a cancer vaccine. Recent studies have reported that metformin, a type 2 diabetes drug, may ameliorate the tumor microenvironment, thereby enhancing anti-tumor immunity. Here, we tested whether the combinational therapeutic strategy of cancer vaccines administered with a heterologous prime-boost strategy with metformin enhanced anti-tumor effects in a melanoma mouse model. The results showed that metformin promoted the transition of M2-tumor-associated macrophages (M2-TAM) to M1-TAM, induced more tumor-infiltrating proliferative CD4 and CD8 T cells, and decreased exhausted T cells. This combinational treatment induced anti-tumor immunity from cancer vaccines, ameliorating the tumor microenvironment, showing improved tumor inhibition, and prolonging survival in tumor-bearing mice compared with either a cancer vaccine or metformin alone.