Microwave ablation combined with PD-L1 blockade synergistically promotes Cxcl9-mediated antitumor immunity.

Although microwave ablation (MWA) is an important curative therapy in colorectal cancer liver metastasis, recurrence still occurs clinically. Our previous studies have shown that the expression of programmed cell death 1 ligand 1 (PD-L1) is upregulated following MWA, suggesting that MWA combined with anti-PD-L1 treatment can serve as a promising clinical therapeutic strategy against cancer. Using MWA-treated preclinical mice models, MWA combined with αPD-L1 treatment decreased tumor growth and prolonged overall survival (OS). Furthermore, through flow cytometry and single-cell RNA sequencing analysis, we determined that the MWA plus αPD-L1 therapy significantly suppressed CD8+ T cell exhaustion and enhanced their effector function. A significant increase in γ-interferon (IFN-γ) stimulated transcription factors, specifically Irf8, was observed. This enhancement facilitated the polarization of tumor-associated macrophages (TAM1s and TAM2s) through the nuclear factor-κB/JAK-STAT1 signaling pathway. Furthermore, the combination therapy stimulated the production of CXC motif chemokine ligand (CXCL9) by TAM1s and tumor cells, potentially increasing the chemotaxis of CD8 T cells and Th1 cells. Knocking out Cxcl9 in MC38 tumor cells or using CXCL9 blockade enhanced tumor growth of untreated tumors and shortened OS. Taken together, our study showed that blocking the IFN-γ-Cxcl9-CD8+ T axis promoted tumor progression and discovered a potential involvement of IRF8-regulated TAMs in preventing T cell exhaustion. Collectively, we identified that the combination of MWA with anti-PD-L1 treatment holds promise as a therapeutic strategy to rejuvenate the immune response against tumors. This merits further exploration in clinical studies.

Foxm1-Mediated Transcriptional Inactivation of NLRP3 Inflammasome Promotes Immunosuppression in Cervical Cancer.

Foxm1 functions as an oncogene in multiple human malignancies, including cervical cancer. However, the potential of Foxm1 in the tumor microenvironment (TME) is still unknown. The purpose of the present study is to investigate the role of Foxm1 in CD8+ T cell anti-tumor immunity. RT-qPCR is conducted to calculate mRNA levels. JASPAR is used to predict the binding sites between Foxm1 and NLRP3. ChIP assay is performed to verify the occupancy of Foxm1 on the promoter of NLRP3. Modulatory relationship between Foxm1 and NLRP3 is verified by luciferase assay. In vivo assays are conducted to further verify the role of Foxm1/NLRP3 axis in cervical cancer. HE staining assay is applied for histological analysis. Flow cytometry is conducted to determine the functions of immune cells. We found that Foxm1 knockdown decreases tumor burden and suppresses tumor growth of cervical cancer. Foxm1 knock-down promotes the infiltration of CD8+ T cells. Foxm1 deficiency inhibits the exhaustion of CD8+ T cells and facilitates the maintenance of CD8+ effector and stem-like T cells. Moreover, Foxm1 transcriptionally inactivates NLRP3 and suppresses the expression of innate cytokines IL-1ß and IL-18. However, inhibition of NLRP3 inflammasome or neutralizing IL-1ß and IL-18 inhibits anti-tumor immunity and promoted tumor growth in Foxm1 deficiency in CD8+ T cells. In summary, targeting Foxm1 mediates the activation of NLRP3 inflammasome and stimulates CD8+ T cell anti-tumor immunity in cervical cancer.

Auricular point acupressure for managing postoperative pain and reducing anxiety in patients with perianal abscesses.

OBJECTIVE: The objective of this study is to assess the efficacy of auricular point acupressure in relieving postoperative pain and reducing anxiety among patients with perianal abscesses. METHODS: We included 61 patients with perianal abscesses who were admitted to the Nantong First People's Hospital between July 2019 and June 2020 and were scheduled to undergo one-stage radical surgery. We divided them into the treatment group (n = 31), where patients were administered preoperative auricular acupressure targeting the bilateral Shenmen, subcortical, and other points. They were instructed to apply pressure five to six times per day, each time for about 3-5 min. Patients in the control group (n = 30) received routine preoperative preparation. The treatment duration for both groups was one week. We compared the two groups using the pain visual analog scale (VAS) scores, the use of additional postoperative analgesics, and scores on the Hamilton anxiety and depression scales pre- and post-surgery at 6 h, 24 h, 48 h, 72 h, and 1 week after surgery, as well as at the time of the first bowel movement. RESULTS: Patients in the treatment group reported lower VAS scores than those of the control group at 48 h, 72 h, 1 week, and at the first defecation post-surgery, and the differences were statistically significant (all P < 0.05). Additional postoperative analgesics were used in seven patients in the treatment group (22.58 %) and in 10 patients in the control group (33.33 %). The difference between the two groups was not statistically significant (χ2 = 0.88, P = 0.35). Postoperative scores for the Hamilton Anxiety Rating Scale (HAM-A) and the Hamilton Depression Rating Scale (HAM-D) in the treatment group were significantly lower than those in the control group (P < 0.05). CONCLUSION: The results of this study demonstrated that auricular point acupressure was effective in alleviating postoperative pain in patients with perianal abscesses and simultaneously reduced their postoperative psychological stress reactions. This dual effect provided both pain relief and a reduction of anxiety with fewer adverse reactions, making it a safe and effective treatment option.