Cellular senescence occurs in proliferating cells as a consequence of various triggers including telomere shortening, DNA damage, and inappropriate expression of oncogenes. The senescent state is accompanied by failure to reenter the cell cycle under mitotic stimulation, resistance to cell death and enhanced secretory phenotype. A growing number of studies have convincingly demonstrated a paradoxical role for spontaneous senescence and therapy-induced senescence (TIS), that senescence may involve both cancer prevention and cancer aggressiveness. Cellular senescence was initially described as a physiological suppressor mechanism of tumor cells, because cancer development requires cell proliferation. However, there is growing evidence that senescent cells may contribute to oncogenesis, partly in a senescence-associated secretory phenotype (SASP)-dependent manner. On the one hand, SASP prevents cell division and promotes immune clearance of damaged cells, thereby avoiding tumor development. On the other hand, SASP contributes to tumor progression and relapse through creating an immunosuppressive environment. In this review, we performed a review to summarize both bright and dark sides of senescence in cancer, and the strategies to handle senescence in cancer therapy were also discussed.

BackgroundThe advent of immune checkpoint therapy has been a tremendous advance in cancer treatment. However, the responses are still insufficient in patients with soft tissue sarcoma (STS). We aimed to identify rational combinations to increase the response to immune checkpoint therapy and improve survival.MethodsWhole-exome sequencing (WES) was performed in 11 patients with liposarcoma. Somatic copy number alterations (SCNAs) were analyzed at the gene level to identify obvious amplification patterns in drug-target genes. The expression and prognostic value of class I histone deacetylases (HDACs) was evaluated in 49 patients with sarcoma in our center and confirmed in 263 sarcoma samples from The Tumor Cancer Genome Atlas (TCGA) database. Q-PCR, flow cytometry and RNA-seq were performed to determine the correlations between class I HDACs, chidamide and PD-L1 in vitro and in vivo. The efficacy of combining chidamide with PD-1 blockade was explored in an immunocompetent murine model and a small cohort of patients with advanced sarcoma. Western blot, ChIP assay and dual luciferase assessment were applied in the mechanistic study.ResultsThe HDAC gene family was frequently amplified in STS. SCNAs in the HDAC gene family were extensively amplified in 8 of 11 (73%) patients with liposarcoma, based on a drug-target gene set, and we verified amplification in 76.65% (197/257) of cases by analyzing TCGA sarcoma cohort. Class I HDAC expression is associated with a poor prognosis for patients with STS, and its inhibition is responsible for promoting apoptosis and upregulating of programmed cell death ligand 1 (PD-L1). The HDAC class I inhibitor chidamide significantly increases PD-L1 expression, increased the infiltration of CD8+ T cells and reduced the number of MDSCs in the tumor microenvironment. The combination of chidamide with an anti-PD-1 antibody significantly promotes tumor regression and improves survival in a murine model. Moreover, chidamide combined with the anti-PD-1 antibody toripalimab is effective in patients with advanced and metastatic sarcoma, and the side effects are tolerable. Mechanistically, chidamide increases histone acetylation at the PD-L1 gene through the activation of the transcriptional factor STAT1.ConclusionsThe combination of chidamide and anti-programmed cell death 1 (PD-1) therapy represents a potentially important strategy for STS.

Introduction:The prognostic values of nutritional and immune-inflammatory indicators in nonmetastatic soft tissue sarcoma (STS) patients are not clear. We investigated the utility of systemic immune-inflammation index (SII) and the high-sensitivity modified Glasgow prognostic score (Hs-mGPS) in the prediction of STS patient's prognosis. Materials and methods: Patients admitted between January 2000 and December 2016, who underwent R0 resection for STS at SYSUCC were carefully retrospectively reviewed, and 454 patients were enrolled. The laboratory data and clinical data were collected from the patient's record. ROC analysis is used to determine the optimal cutoff value. Survival curves were analysed by Kaplan-Meier method. Cox proportional hazard model was used to find out prognostic variables. Results: Increased SII and Hs-mGPS values were significantly related to larger tumour size, deep tumour location, higher tumour grade and more advanced American Joint Committee on Cancer (AJCC) stage. Patients with an elevated SII had a shorter median survival time and a lower 5-year OS rate than those with a low SII. And patients with low Hs-mGPS had longer median OS and DFS. Multivariate analysis revealed that both the SII and the Hs-mGPS were independent predictive indicators for OS. And a joint model containing both the Hsm-GPS and the SII appeared to have the strongest predictive ability. Conclusion: Our findings indicated that malnutrition and systemic inflammation are risk factors for the survival of STS patients after operation, and early recognition and intervention of malnutrition and systemic inflammation may help to improve the survival of the patients.

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Objective The purpose of this retrospective study was to identify the prognostic significance of time to local recurrence (TLR) with regard to overall survival (OS) and survival after local recurrence (SAR) in patients with soft tissue sarcoma (STS) of the extremity and abdominothoracic wall. Methods We identified 477 patients who underwent R0 resection for localized STS of the extremity and abdominothoracic wall, from January 1995 to December 2016, of whom 190 patients developed local recurrence as their first recurrent event. Based on TLR, patients were divided into two groups: early local recurrence (ELR, <12 months) and late local recurrence (LLR, ≥12 months). The Kaplan–Meier method and Cox regression analysis were used to estimate the OS and SAR, and to identify factors associated with patient outcomes. Results The median follow-up time for the entire cohort was 118.4 months, and was 118.5 months for the 190 patients who developed local recurrence. Deep tumor location (HR 1.73, 95% CI 1.27–2.37, P = 0.001) and tumor grade ≥2 (G2 vs. G1: HR 1.75, 95% CI 1.21–2.53, G3 vs. G1: HR 2.57, 95% CI 1.66–3.98, P < 0.001) were associated with a higher rate of local recurrence. There were 99 patients in the ELR group and 91 in the LLR group, with a median TLR of 10.8 months for the entire cohort. Patients from the ELR group had a shorter OS and a lower 5-year OS rate than the LLR group. Univariate and multivariate analyses demonstrated TLR as an independent prognostic factor for SAR and OS, in addition to tumor grade. Also, surgical treatment and absence of metastasis after local recurrence were associated with longer SAR. Conclusions In patients with STS of the extremity and abdominothoracic wall, ELR after R0 resection indicated a worse prognosis than those with LLR, and TLR can be considered an independent prognostic factor for OS and SAR. Furthermore, local recurrence was significantly influenced by the depth and the histopathological grading of the primary tumor, and reoperation after local recurrence could improve survival, which means salvage surgery may still be the preferred treatment when there are surgical indications after recurrence.