Novel promising strategies for combination with sorafenib are urgently needed to enhance its clinical benefit and overcome toxicity in hepatocellular carcinoma (HCC). the molecular and immunomodulatory antitumor effects of sorafenib alone and in combination with the new immunotherapeutic agent R848 are presented. Syngeneic HCC mouse model is presented to explore the antitumor effect and safety of three sorafenib doses alone, R848 alone, or their combination in vivo. R848 significantly enhances the sorafenib antitumor activity at a low subclinical dose with no obvious toxic side effects. Furthermore, the combination therapy reprograms the tumor immune microenvironment by increasing antitumor macrophages and neutrophils and preventing immunosuppressive signaling. Combination treatment promotes classical M1 macrophage‐to‐FTH1high M1 macrophage transition. The close interaction between neutrophils/classical M1 macrophages and dendritic cells promotes tumor antigen presentation to T cells, inducing cytotoxic CD8+ T cell‐mediated antitumor immunity. Additionally, low‐dose sorafenib, alone or combined with R848, normalizes the tumor vasculature, generating a positive feedback loop to support the antitumor immune environment. Therefore, the combination therapy reprograms the HCC immune microenvironment and normalizes the vasculature, improving the therapeutic benefit of low‐dose sorafenib and minimizing toxicity, suggesting a promising novel immunotherapy (R848) and targeted therapy (tyrosine kinase inhibitors) combination strategy for HCC treatment.

BackgroundBreast cancer is the most common cancer type for females and has the highest relative number of suicide cases among female-specific cancers. This study aimed to demonstrate suicide rates and changing trends and to identify risk factors for suicide among female breast cancer survivors.MethodsData were derived from the surveillance, epidemiology, and end results database for women diagnosed with breast cancer from 2000 to 2017. Mortality rate and standardized mortality ratios (SMRs) were calculated to describe the incidence rate and trend of suicide among female breast cancer survivors. Gray’s test and cumulative incidence function (CIF) curves were used to assess difference of cumulative suicide incidence in subgroups. Multivariate Fine-Gray competing risk model was used to identify risk factors for individual survivors and nomogram model was used to estimate the probability of suicide.ResultThere were 414 suicide cases among 638,547 female breast cancer survivors observed for 5,079,194 person-years, and the suicide rate and SMRs gradually increased with the year of diagnosis. Female breast cancer survivors had a higher risk of suicide than the general population (SMR = 1.19; 95% CI (1.08–1.31)). Based on the result of Fine-Gray competing risk models, age group (50-70 vs <50: HR=0.65, 95% CI:0.52-0.80; >70 vs <50: HR=0.22, 95% CI:0.15-0.32), race/ethnicity (black vs white: HR= 0.20, 95% CI: 0.11-0.36; other race vs white: HR= 0.67, 95% CI: 0.46-0.97), marital status (separated vs married: HR= 1.50, 95% CI: 1.16-1.94; single vs married: HR= 1.70, 95% CI: 1.31-2.20), stage (distant vs regional: HR= 0.30, 95% CI: 0.14-0.63), radiotherapy (Yes vs No/Unknown: HR= 0.62, 95% CI: 0.49-0.77), and molecular subtypes (HER-2 vs Luminal B (HR= 2.53, 95% CI: 1.10-5.82), TNBC vs Luminal B (HR= 2.11, 95% CI: 1.01-4.42)) were independent predictors of suicide among female breast cancer patients. A nomogram was constructed to predict the suicide probability for individual survivors with a C-index of 0.62 (95%CI: 0.59-0.66).ConclusionFemale breast cancer survivors with younger age (less than 50 years old), white race, unmarried status, regional stage, HER-2 or TNBC subtype, and no radiotherapy performed were more likely to commit suicide. The clinicians and family members should pay more attention to patients with high risk factors of suicide to decrease the mortality rate.

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Growth differentiation factor 15 (GDF15) is a pleiotropic cytokine, which is involved in the cellular stress response following acute damage. However, the functional role of GDF15 in triple-negative breast cancer (TNBC) has not been fully elucidated. ELISA, Western blot, and PCR assays as well as bioinformatics analyses were conducted to observe the expression of GDF15. Cell Counting Kit-8, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and crystal violet staining assays were conducted to evaluate paclitaxel resistance and cell viability. Cell apoptosis was analyzed by Western blotting. Murine xenograft model assay was employed to evaluate tumor growth in vivo. Our data indicate that GDF15 is markedly elevated in paclitaxel-resistant TNBC cells, which is significantly associated with unfavorable prognosis. Silencing of GDF15 robustly inhibits the proliferation of tumor cells and increases their sensitivity to paclitaxel in vitro and in vivo, whereas the treatment of purified GDF15 protein confers breast cancer cells with chemoresistance ability. Moreover, GDF15 activates protein kinase B (AKT) /mammalian target of rapamycin (mTOR) signaling, inhibition of AKT or mTOR reverses the prosurvival effect of GDF15 and enhances the antitumor efficacy of paclitaxel in TNBC cells. Altogether, our study uncovers the role of GDF15 in tumor growth and paclitaxel resistance, implicating a potential therapeutic target for TNBC.