Cancer-educated neutrophils promote lung cancer progression via PARP-1-ALOX5-mediated MMP-9 expression

Objective:Neutrophils are one of the most predominant infiltrating leukocytes in lung cancer tissues and are associated with lung cancer progression.How neutrophils promote lung cancer progression,however,has not been established.Methods:Kaplan–Meier plotter online analysis and tissue immunohistochemistry were used to determine the relationship between neutrophils and overall survival in lung cancer patients.The effect of neutrophils on lung cancer was determined using the Transwell migration assay,a proliferation assay,and a murine tumor model.Gene knockdown was used to determine poly ADPribose polymerase(PARP)-1 function in lung cancer-educated neutrophils.Western blot analysis and gelatin zymography were used to demonstrate the correlation between PARP-1 and matrix metallopeptidase 9(MMP-9).Immunoprecipitation coupled to mass spectrometry(IP/MS)was used to identify the proteins interacting with PARP-1.Co-immunoprecipitation(Co-IP)was used to confirm that PARP-1 interacts with arachidonate 5-lipooxygenase(ALOX5).Neutrophil PARP-1 blockage by AG14361 rescued neutrophil-promoted lung cancer progression.Results:An increased number of infiltrating neutrophils was negatively associated with overall survival in lung cancer patients(P<0.001).Neutrophil activation promoted lung cancer cell invasion,migration,and proliferation in vitro,and murine lung cancer growth in vivo.Mechanistically,PARP-1 was shown to be involved in lung cancer cell-induced neutrophil activation to increase MMP-9 expression through interacting and stabilizing ALOX5 by post-translational protein modification(PARylation).Blocking PARP-1 by gene knockdown or AG14361 significantly decreased ALOX5 expression and MMP-9 production,and eliminated neutrophil-mediated lung cancer cell invasion and in vivo tumor growth.Conclusion:We identified a novel mechanism by which PARP-1 mediates lung cancer cell-induced neutrophil activation and PARylates ALOX5 to regulate MMP-9 expression,which exacerbates lung cancer progression.

PD-L1翻译后修饰的研究进展

高表达免疫检查点分子程序性死亡受体-配体1(programmed death ligand-1,PD-L1)是肿瘤细胞逃避机体免疫监视的重要途径。PD-L1的表达受到转录水平、翻译水平和翻译后修饰水平等的调控。近年来,PD-L1翻译后修饰逐渐成为PD-L1研究领域的热点。PD-L1的翻译后修饰包括糖基化、泛素化、磷酸化、棕榈酰化和乙酰化等,可影响PD-L1的稳定性及生物学功能。本文将对该领域的研究进展进行综述,以期为肿瘤免疫治疗研究提供新思路。

Clinical role of ^(18)F-FDG PET/CT-based simultaneous modulated accelerated radiotherapy treatment planning for locally advanced nasopharyngeal carcinoma

Objective The aim of this study was to compare the long-term local control, overall survival, and late toxicities of positron emission tomography/computed tomography （PET/CT）-guided dose escalation radio- therapy versus conventional radiotherapy in the concurrent chemoradiotherapy treatment of locally ad- vanced nasopharyngeal carcinoma （NPC）. Methods Atotal of 48 patients with stage IIl-IVa NPC were recruited and randomly administered PET/CT- guided dose escalation chemoradiotherapy （group A） or conventional chemoradiotherapy （group B）. The dose-escalation radiotherapy was performed using the simultaneous modulated accelerated radiotherapy technique at prescribed doses of 77 gray （Gy） in 32 fractions （f） to the gross target volume （GTV）： planning target volume （PTV） 1 received 64 Gy/32 f, while PTV2 received 54.4 Gy/32 f. Patients in group B received uniform-dose intensity-modulated radiotherapy, PTV1 received 70 Gy/35 f and PTV2 received 58 Gy/29 f. Concurrent chemotherapy consisted of cisplatin [20 mg/m2 intravenous （IV） on days 1-4] and docetaxel （75 mg/m2 IV on days 1 and 8） administered during treatment weeks 1 and 4. All patients received 2-4 cycles of adjuvant chemotherapy of the same dose and drug regimen. Results The use of fluorine-18-fluorodeoxyglucose （18F-FDG） PET/CT significantly reduced the treat- ment volume delineation of the GTV in 83.3% （20/24） of patients. The 5-year local recurrence-free survival rates of the two groups were 100% and 79.2%, respectively （P = 0.019）. The 5-year disease free survival （DFS） rates were 95.8% and 75.0%, respectively （P = 0.018）. The 5-year local progression-free survival and DFS rates were significantly different. The 5-year overall survival （OS） rates were 95.8% and 79.2%, re- spectively. Differences in OS improvement were insignificant （P = 0.079）. Late toxicities were similar in the two groups. The most common late toxicities of the two arms were grade 1-2 skin dystrophy, xerostomia, subcutaneous fibrosis, and hearing loss. There were no cases of grade 4 late toxicity. Conclusion The use of 18F-FDG PET/CT-guided dose escalation radiotherapy is well tolerated and can reduce local recurrence rates for patients with locally advanced NPC compared to conventional chemora- diotherapy.

BCMA-CD19 bispecific CAR-T therapy in refractory chronic inflammatory demyelinating polyneuropathy

Chronic inflammatory demyelinating polyneuropathy(CIDP)is a rare immune-mediated disease characterized by refractory and relapsed peripheral nerve and nerve root damage,leading to severe sequelae for patients.Although glucocorticoids,intravenous immunoglobulin(IVIg),and immunosuppressive agents are recommended for treating CIDP and preventing relapses,some patients’conditions cannot be effectively controlled.Due to the uncertain efficacy and toxicity issues of broad-spectrum immune-modulatory or suppressive drugs,developing a safe and effective treatment strategy is warranted.

A p53/CPEB2 negative feedback loop regulates renal cancer cell proliferation and migration

The tumor suppressor p53 transactivates the expression of multiple genes to exert its multifaceted functions and ultimately maintains genome stability.Thus,cancer cells develop various mechanisms to diminish p53 expression and bypass the cell cycle checkpoint.In this study,we identified the gene encoding RNAbinding protein cytoplasmic polyadenylation element-binding protein 2(CPEB2)as a p53 target.In turn,CPEB2 decreases p53 messenger RNA stability and translation to fine-tune p53 level.Specifically,we showed that CPEB2 binds the cytoplasmic polyadenylation elements in the p5330-untranslated region,and the RNA recognition motif and zinc finger(ZF)domains of CPEB2 are required for this binding.Furthermore,we found that CPEB2 was upregulated in renal cancer tissues and promotes the renal cancer cell proliferation and migration.The oncogenic effect of CPEB2 is partially dependent on negative feedback regulation of p53.Overall,we identify a novel regulatory feedback loop between p53 and CPEB2 and demonstrate that CPEB2 promotes tumor progression by inactivating p53,suggesting that CPEB2 is a potential therapeutic target in human renal cancer.

Overexpression of CIP2A is associated with poor prognosis in multiple myeloma

Cancerous inhibitor of protein phosphatase 2A(CIP2A),an endogenous protein phosphatase 2A(PP2A)inhibitor,has been identified as an oncoprotein in promoting cancer initiation and progression of several types of cancer.However,the expression and the role played by CIP2A in the pathogenesis of multiple myeloma(MM)remain unclear.In this study,we showed that CIP2A was overexpressed in human MM cell lines and MM patients’bone marrow tissues.Clinicopathologic analysis showed that CIP2A expression was significantly correlated with clinical stage and percent of plasma cells in bone marrow.Kaplan–Meier analysis revealed that patients with high CIP2A expression presented with poorer overall survival rates than those with low CIP2A expression.Moreover,CIP2A knockdown in MM cells resulted in attenuated proliferative abilities.In addition,CIP2A depletion sensitizes dexamethasone(Dex)-resistant cells to Dex.The effect of CIP2A on proliferation and Dex therapy was mediated by the inhibition of PP2A,which in turn activated Akt.In vivo studies confirmed that CIP2A regulated MM tumorigenesis and the phosphorylation of Akt.Taken together,our results suggest that CIP2A oncoprotein plays an important role in MM progression and could serve as a prognosis marker and a novel therapeutic target for the treatment of patients with MM.

The SKI proto-oncogene restrains the resident CD103^(+)CD8^(+) T cell response in viral clearance

Acute viral infection causes illness and death.In addition,an infection often results in increased susceptibility to a secondary infection,but the mechanisms behind this susceptibility are poorly understood.Since its initial identification as a marker for resident memory CD8^(+)T cells in barrier tissues,the function and regulation of CD103 integrin(encoded by ITGAE gene)have been extensively investigated.Nonetheless,the function and regulation of the resident CD103^(+)CD8^(+)T cell response to acute viral infection remain unclear.Although TGFβsignaling is essential for CD103 expression,the precise molecular mechanism behind this regulation is elusive.Here,we reveal a TGFβ–SKI–Smad4 pathway that critically and specifically directs resident CD103^(+)CD8^(+)T cell generation for protective immunity against primary and secondary viral infection.We found that resident CD103^(+)CD8^(+)T cells are abundant in both lymphoid and nonlymphoid tissues from uninfected mice.CD103 acts as a costimulation signal to produce an optimal antigenic CD8^(+)T cell response to acute viral infection.There is a reduction in resident CD103^(+)CD8^(+)T cells following primary infection that results in increased susceptibility of the host to secondary infection.Intriguingly,CD103 expression inversely and specifically correlates with SKI proto-oncogene(SKI)expression but not R-Smad2/3 activation.Ectopic expression of SKI restricts CD103 expression in CD8^(+)T cells in vitro and in vivo to hamper viral clearance.Mechanistically,SKI is recruited to the Itgae loci to directly suppress CD103 transcription by regulating histone acetylation in a Smad4-dependent manner.Our study therefore reveals that resident CD103^(+)CD8^(+)T cells dictate protective immunity during primary and secondary infection.Interfering with SKI function may amplify the resident CD103^(+)CD8^(+)T cell response to promote protective immunity.