Background Dendritic cells (DCs) are central for the initiation and regulation of innate and adaptive immunity in the tumor microenvironment. As such, many kinds of DC-targeted vaccines have been developed to improve cancer immunotherapy in numerous clinical trials. Targeted delivery of antigens and adjuvants to DCs in vivo represents an important approach for the development of DC vaccines. However, nonspecific activation of systemic DCs and the preparation of optimal immunodominant tumor antigens still represent major challenges. Methods We loaded the immunogenic cell death (ICD) inducers human neutrophil elastase (ELANE) and Hiltonol (TLR3 agonist) into α-lactalbumin (α-LA)-engineered breast cancer-derived exosomes to form an in situ DC vaccine (HELA-Exos). HELA-Exos were identified by transmission electron microscopy, nanoscale flow cytometry, and Western blot analysis. The targeting, killing, and immune activation effects of HELA-Exos were evaluated in vitro. The tumor suppressor and immune-activating effects of HELA-Exos were explored in immunocompetent mice and patient-derived organoids. Results HELA-Exos possessed a profound ability to specifically induce ICD in breast cancer cells. Adequate exposure to tumor antigens and Hiltonol following HELA-Exo-induced ICD of cancer cells activated type one conventional DCs (cDC1s) in situ and cross-primed tumor-reactive CD8+ T cell responses, leading to potent tumor inhibition in a poorly immunogenic triple negative breast cancer (TNBC) mouse xenograft model and patient-derived tumor organoids. Conclusions HELA-Exos exhibit potent antitumor activity in both a mouse model and human breast cancer organoids by promoting the activation of cDC1s in situ and thus improving the subsequent tumor-reactive CD8+ T cell responses. The strategy proposed here is promising for generating an in situ DC-primed vaccine and can be extended to various types of cancers. Graphic Abstract Scheme 1. Schematic illustration of HELA-Exos as an in situ DC-primed vaccine for breast cancer. (A) Allogenic breast cancer-derived exosomes isolated from MDA-MB-231 cells were genetically engineered to overexpress α-LA and simultaneously loaded with the ICD inducers ELANE and Hiltonol (TLR3 agonist) to generate HELA-Exos. (B) Mechanism by which HELA-Exos activate DCs in situ in a mouse xenograft model ofTNBC. HELA-Exos specifically homed to the TME and induced ICD in cancer cells, which resulted in the increased release of tumor antigens, Hiltonol, and DAMPs, as well as the uptake of dying tumor cells by cDC1s. The activated cDC1s then cross-primed tumor-reactive CD8+ T cell responses. (C) HELA-Exos activated DCs in situ in the breast cancer patient PBMC-autologous tumor organoid coculture system. Abbreviations: DCs: dendritic cells; α-LA: α-lactalbumin; HELA-Exos: Hiltonol-ELANE-α-LA-engineered exosomes; ICD: immunogenic cell death; ELANE: human neutrophil elastase; TLR3: Toll-like receptor 3; TNBC: triple-negative breast cancer; TME: tumor microenvironment; DAMPs: damage-associated molecular patterns; cDC1s: type 1 conventional dendritic cells; PBMCs: peripheral blood mononuclear cells

Objective: To compare the efficacy and safety of biologics for patients with moderate to severe plaque psoriasis. Methods: We systematically reviewed 60 randomized controlled trials (34,020 participants), which compared 14 biological drugs for treatment of moderate to severe plaque psoriasis. The main assessment criteria were ≥ 90 % reductions in Psoriasis Area and Severity Index (PASI 90) and the number of patients who reported treatment-emergent adverse events (AEs). Secondary criteria were ≥ 75 % reductions in Psoriasis Area and Severity Index (PASI 75), Physician's Global Assessment 0/1 (PGA 0/1) and infections. Results: This network meta-analysis showed that biologics were significantly more effective than placebo. Ixekizumab, risankizumab, and bimekizumab were among the most effective treatments, and tildrakizumab, guselkumab and risankizumab were better than the other drugs with respect to safety. Risankizumab and guselkumab performed relatively stable with respect to both efficacy and safety. At the class level, blockers of interleukin (IL)-17A showed favorable efficacy while inhibitors of the p19 subunit of IL-23 were best tolerated of all efficient biologics. Conclusions: Ixekizumab was the most effective biologic in PASI 90, while IL-23p19 inhibitors, risankizumab and guselkumab performed relatively stable with respect to efficacy and safety.

As a pleiotropic cytokine, interleukin-6 (IL-6) not only regulates the cellular immune response, but it also promotes tumor development by activating multiple carcinogenic pathways. IL-6 expression is significantly elevated in colorectal cancer (CRC) and is closely related to CRC development and patient prognosis. In CRC, IL-6 activates signal transducers and activators of transduction-3 (STAT3) to promote tumor initiation and tumor growth. IL-6/STAT3 signalling has a profound effect on tumor-infiltrating immune cells in the tumor immune microenvironment in CRC. Additionally, IL-6/STAT3 pathway activates downstream target genes to protect tumor cells from apoptosis; drive tumor cell proliferation, cell cycle progression, invasion and metastasis; promote tumor angiogenesis; and stimulate drug resistance. Therefore, a thorough understanding of the many effects of the IL-6/STAT3 pathway in CRC is needed, which the present review examines.

Foxp3 is a specific marker for regulatory T cells (Tregs), and interleukin (IL)-17 is the signature cytokine of T-helper (Th) 17 cells. Recent studies suggested that Foxp3+ Tregs and IL-17+ Th17 cells may be involved in pathogenesis of lichen planus (LP). The objectives of this study were to examine the immunoexpression of Foxp3 and IL-17 in archival paraffin-embedded biopsy specimens from 80 cases of LP (oral LP, n = 42; cutaneous LP, n = 38) and compare against normal control tissues (oral mucosa, n = 10; skin, n = 10). The results showed that the mean number of Foxp3 and IL-17 expression in LP was significantly higher compared to controls, respectively (both P < 0.001). A positive correlation between Foxp3 and IL-17 expression (r = 0.273; P = 0.014) was observed. Moreover, the mean number of Foxp3 expression in oral LP was significantly higher than cutaneous LP (P < 0.001). Collectively, our findings demonstrated the increased expression of Foxp3 and IL-17 in LP lesions including oral and cutaneous variants. Foxp3 expressing in oral LP was higher than cutaneous LP, which may be associated with the difference in clinical behaviour of the two variants of the disease. Further studies are required to investigate the immunopathologic mechanisms and therapeutic target of Foxp3+ Tregs and IL-17+ Th17 cells in LP.

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