Over-expression of programmed death-ligand 1 and programmed death-1 on antigen-presenting cells as a predictor of organ dysfunction and mortality during early sepsis: a prospective cohort study

BACKGROUND:This study aimed to explore the changes of programmed death-ligand 1(PDL1)and programmed death-1(PD-1)expression on antigen-presenting cells(APCs)and evaluate their association with organ failure and mortality during early sepsis.METHODS:In total,40 healthy controls and 198 patients with sepsis were included in this study.Peripheral blood was collected within the first 24 h after the diagnosis of sepsis.The expression of PDL1 and PD-1 was determined on APCs,such as B cells,monocytes,and dendritic cells(DCs),by flow cytometry.Cytokines in plasma,such as interferon-γ(IFN-γ),tumor necrosis factor-α(TNF-α),interleukin-4(IL-4),IL-6,IL-10,and IL-17A were determined by Luminex assay.RESULTS:PD-1 expression decreased significantly on B cells,monocytes,myeloid DCs(mDCs),and plasmacytoid DCs(pDCs)as the severity of sepsis increased.PD-1 expression was also markedly decreased in non-survivors compared with survivors.In contrast,PD-L1 expression was markedly higher on mDCs,pDCs,and monocytes in patients with sepsis than in healthy controls and in non-survivors than in survivors.The PD-L1 expression on APCs(monocytes and DCs)was weakly related to organ dysfunction and infl ammation.The area under the receiver operating characteristic curve(AUC)of the PD-1 percentage of monocytes(monocyte PD-1%)+APACHE II model(0.823)and monocyte PD-1%+SOFA model(0.816)had higher prognostic value than other parameters alone.Monocyte PD-1%was an independent risk factor for 28-day mortality.CONCLUSION:The severity of sepsis was correlated with PD-L1 or PD-1 over-expression on APCs.PD-L1 in monocytes and DCs was weakly correlated with infl ammation and organ dysfunction during early sepsis.The combination of SOFA or APACHE II scores with monocyte PD-1%could improve the prediction ability for mortality.

Expression and clinical value of programmed cell death-ligand 1(PD-L1)in diffuse large B cell lymphoma:a retrospective study

Background: The programmed cell death-1(PD-1)/programmed cell death-ligand 1(PD-L1) pathway inhibits the activation of T cells and plays a crucial role in the negative regulation of cellular and humoral immune responses.Diffuse large B-cell lymphoma(DLBCL) is the most common lymphoid malignancy in adults. In the present study, we aimed to detect the expression of PD-L1 in DLBCL and to analyze its relationship with prognosis.Methods: We reviewed medical records of 204 newly diagnosed DLBCL patients in Sun Yat-sen University Cancer Center between October 2005 and August 2012. The expression of PD-L1 in tumor tissues from these 204 patients was detected using immunohistochemical(IHC) assay. The expression of anaplastic lymphoma kinase(ALK), CD5,CD30, and C-Myc in tumor specimens from 109 patients was detected using IHC, and Epstein-Barr virus(EBV)-encoded RNAs(EBERs) were detected using fluorescence in situ hybridization. The Spearman method was used for correlation analysis. The Kaplan-Meier method with log-rank test was used for univariate analysis. Cox proportional hazards model was used for multivariate analysis.Results: Of the 204 patients, 100(49.0%) were PD-L1-positive in tumor cells and 44(21.6%) were PD-L1-positive in tumor microenvironment. PD-L1 expression in tumor cells and tumor microenvironment were more common in the non-germinal center B-cell-like(GCB) subtype than in the GCB subtype(P = 0.02 and P= 0.04). Patients with PD-L1 expression in tumor microenvironment were more likely to be resistant to first-line chemotherapy when compared with the patients without PD-L1 expression in tumor microenvironment(P = 0.03). PD-L1 expression in tumor microenvironment was negatively correlated with C-Myc expression(r =-0.20, P = 0.04). No correlations were detected between PD-L1 expression and the expression of ALK, CD5, and CD30 as well as EBERs. The 5-year overall survival(OS)rates were 50.0% and 67.3% in patients with and without PD-L1 expression in tumor cells(P = 0.02). PD-L1 expression in tumor cells was an independent risk predictor for OS(P < 0.01).Conclusions: PD-L1 expression is more common in the non-GCB subtype than in the GCB subtype. PD-L1 expression in tumor microenvironment has a negative correlation with C-Myc. PD-L1 positivity predicts short survival in DLBCL patients. For patients with PD-L1 expression, more strategy such as anti-PD-L1 antibody treatment should be recommended.

Prognostic value of programmed death.1, programmed death-ligand 1, programmed death-ligand 2 expression, and CD8(+) T cell density in primary tumors and metastatic lymph nodes from patients with stage T1.4N+M0 gastric adenocarcinoma

Background: Anti-programmed death-1/programmed death-ligand 1(PD-1/PD-L1) immunotherapy has been proved to be effective on gastric cancer in ongoing clinical trials. However, the value of PD-L1 in predicting responses of patients with gastric cancer to anti-PD-1/PD-L1 immunotherapy is controversial. Some studies suggested that intra-and inter-tumoral heterogeneity of PD-L1 expression might explain the controversy.This study aimed to analyze the expression of PD-L1, PD-L2, and PD-1 as well as CD8(+) T-cell density in primary tumors and lymph nodes from patients with stage T1-4 N+M0 gastric adenocarcinoma to explore the heterogeneity of PD-1 signaling pathway molecules.Methods: In primary tumors and metastatic as well as non-metastatic lymph nodes from patients with stage T1-4 N+M0 gastric adenocarcinoma, we detected PD-L1 and PD-L2 expression with immunohistochemistry. CD8(+)T-cell density in primary tumors and PD-1 expression on CD8(+)T cells were detected with immunofluorescence. Univariate analysis was used to determine the prognostic values of them. Cox proportional hazard regression model was used to identify independent risk factors that affect patients' overall survival and disease-free survival.Results: Among 119 eligible patients who had undergone surgical resection, the positive rate of PD-L1 was higher in metastatic lymph nodes than in primary tumors(45.4% vs. 38.7%, P = 0.005); the positive rate of PD-1 on CD8(+)T cells was significantly higher in primary tumors and metastatic lymph nodes than in tumor-free lymph nodes(both P < 0.001). The intensity of PD-1 expression on CD8(+) T cells in primary tumors and in metastatic lymph nodes were stronger than that in tumor-free lymph nodes from the same patient. Beside, the positive rate of PD-L2 did not show any differences between primary tumors and metastatic lymph nodes. In multivariate analysis, PD-L1 expression,PD-L2 expression, a low density of CD8(+) T cells in primary tumors, and PD-1 expression on CD8(+) T cells in primary tumors were associated with poor prognosis.Conclusion: The expression of PD-L1 is heterogeneous in primary tumors and in metastatic lymph nodes from patients with stageT1-4 N+M0 gastric adenocarcinoma, which might explain the inconsistent results in assessing the prognostic value of PD-L1 expression in previous studies.

IMpower210:A phase Ⅲ study of second-line atezolizumab vs. docetaxel in East Asian patients with non-small cell lung cancer

Objective: IMpower210(NCT02813785) explored the efficacy and safety of single-agent atezolizumab vs.docetaxel as second-line treatment for advanced non-small cell lung cancer(NSCLC) in East Asian patients.Methods: Key eligibility criteria for this phase Ⅲ, open-label, randomized study included age ≥18 years;histologically documented advanced NSCLC per the Union for International Cancer Control/American Joint Committee on Cancer staging system(7th edition);Eastern Cooperative Oncology Group performance status of 0 or 1;and disease progression following platinum-based chemotherapy for advanced or metastatic NSCLC. Patients were randomized 2:1 to receive either atezolizumab(1,200 mg) or docetaxel(75 mg/m^(2)). The primary study endpoint was overall survival(OS) in the intention-to-treat(ITT) population with wild-type epidermal growth factor receptor expression(ITT EGFR-WT) and in the overall ITT population.Results: Median OS in the ITT EGFR-WT population(n=467) was 12.3 [95% confidence interval(95% CI),10.3-13.8] months in the atezolizumab arm(n=312) and 9.9(95% CI, 7.8-13.9) months in the docetaxel arm[n=155;stratified hazard ratio(HR), 0.82;95% CI, 0.66-1.03]. Median OS in the overall ITT population was 12.5(95% CI, 10.8-13.8) months with atezolizumab treatment and 11.1(95% CI, 8.4-14.2) months(n=377) with docetaxel treatment(n=188;stratified HR, 0.87;95% CI, 0.71-1.08). Grade 3/4 treatment-related adverse events(TRAEs) occurred in 18.4% of patients in the atezolizumab arm and 50.0% of patients in the docetaxel arm.Conclusions: IMpower210 did not meet its primary efficacy endpoint of OS in the ITT EGFR-WT or overall ITT populations. Atezolizumab was comparatively more tolerable than docetaxel, with a lower incidence of grade3/4 TRAEs.

Clinical significance of programmed cell death-ligand expression in small bowel adenocarcinoma is determined by the tumor microenvironment

BACKGROUND Comprehensive genomic analysis has shown that small bowel adenocarcinoma(SBA)has different genomic profiles from gastric and colorectal cancers.Hence,it is essential to establish chemotherapeutic regimens based on SBA characteristics.The expression of programmed cell death-ligand 1(PD-L1)and programmed cell death-ligand 2(PD-L2)in SBA is not fully understood.Anti-PD-L1/PD-1 therapy uses tumor-infiltrating lymphocytes(TILs);therefore,the status of TILs in the tumor microenvironment(TME)may influence their efficacy.The ratio of FoxP3+to CD8+T cells has been reported to be useful in predicting the prognosis of digestive system cancers.AIM To investigate the clinicopathological significance of PD-L1/2 expression according to the status of TILs in SBA tissues.METHODS We performed immunohistochemical analysis for PD-L1,PD-L2,CD8,FoxP3,and DNA mismatch repair(MMR)proteins using formalin-fixed,paraffin-embedded tissues from 50 patients diagnosed with primary SBA.The immunoreactivities of PD-L1 and PD-L2 were determined separately in tumor cells and tumor-infiltrating immune cells throughout the tumor center and invasive margins,and finally evaluated using the combined positive score(CPS).We assessed CD8+and FoxP3+T cells in the intratumoral and tumor-surrounding stroma.Subsequently,we calculated and summed the ratio of FoxP3 to CD8+T cell counts.Immune-related cell densities were graded as low or high.Immunohistochemical results were compared with clinicopathological factors and patient prognosis.The distribution of cancer-specific survival(CSS)was estimated using the Kaplan–Meier method,and the log-rank test was used to test for significant differences in CSS.A Cox proportional hazard model was also used to assess the effect of tumor variables on CSS.RESULTS PD-L1 expression was positive in 34%in tumor cells(T-PD-L1)and 54%in tumor-infiltrating immune cells(I-PDL1)of the cases examined.T-PD-L2 was positive in 34%and I-PD-L2 was positive in 42%of the cases.PD-L1 CPS≥10 and PD-L2 CPS≥10 were observed in 50%and 56%of the cases,respectively.Deficient MMR(dMMR)was 14%of the cases.T-PD-L1,I-PD-L1 and PD-L1 CPS≥10 were all significantly associated with dMMR(P=0.037,P=0.009,and P=0.005,respectively).T-PD-L1,I-PD-L1,and PD-L1 CPS≥10 were all associated with deeper depth of invasion(P=0.001,P=0.024,and P=0.002,respectively).I-PD-L2 expression and PD-L2 CPS≥10 were significantly higher in the differentiated histological type(P=0.015 and P=0.030,respectively).The I-PD-L1 and IPD-L2 levels were significantly associated with better CSS(P=0.037 and P=0.015,respectively).CD8-high was significantly associated with less lymph node metastasis(P=0.047),less distant metastasis(P=0.024),less peritoneal dissemination(P=0.034),and earlier TNM stage(P=0.047).The CD8-high group had better prognosis than the CD8-low group(P=0.018).FoxP3 expression was not associated with any clinicopathological factors or prognosis.We found that patients with PD-L2 CPS≥10 tended to have worse prognosis in the FoxP3/CD8-low group(P=0.088).CONCLUSION The clinicopathological significance of PD-L1/2 expression may differ depending on the TME status.Immune checkpoint inhibitors may improve the prognosis of SBA patients with low FoxP3/CD8 ratio and PD-L2 expression.

Anti program death-1/anti program death-ligand 1 in digestive cancers

Human tumors tend to activate the immune system regulatory checkpoints as a means of escaping immunosurveillance. For instance, interaction between program death-1(PD-1) and program death-ligand 1(PD-L1) will lead the activated T cell to a state of anergy. PD-L1 is upregulated on a wide range of cancer cells. Anti-PD-1 and anti-PD-L1 monoclonal antibodies(m Abs), called immune checkpoint inhibitors(ICIs), have consequently been designed to restore T cell activity. Accumulating data are in favor of an association between PD-L1 expression in tumors and response to treatment. A PD-L1 expression is present in 30% to 50% of digestive cancers. Multiple anti-PD-1(nivolumab, pembrolizumab) and anti-PD-L1 m Abs(MPDL3280A, Medi4736) are under evaluation in digestive cancers. Preliminary results in metastatic gastric cancer with pembrolizumab are highly promising and phase Ⅱ will start soon. In metastatic colorectal cancer(CRC), a phase Ⅲ trial of MPDL3280 A as maintenance therapy will shortly be initiated. Trials are also ongoing in metastatic CRC with high immune T cell infiltration(i.e., microsatellite instability). Major challenges are ahead in order to determine how, when and for which patients we should use these ICIs. New radiologic criteria to evaluate tumor response to ICIs are awaiting prospective validation. The optimal therapeutic sequence and association with cytotoxic chemotherapy needs to be established. Finally, biomarker identification will be crucial to selection ofpatients likely to benefit from ICIs.

抗PD-L1治疗在大鼠淋巴管畸形模型中的作用

目的:通过大鼠淋巴管畸形(lymphatic malformations,LM)动物模型,探讨抗PD-L1(programmed death ligand 1)治疗在淋巴管畸形中的作用。方法:选择20只雌性成年Wistar大鼠,体重(250±30)g,在颈部皮下注射弗氏不全佐剂(Freund's incomplete adjuvant,FIA)构建大鼠LM动物模型。然后分成4组:PBS组、抗PD-L1组、LPS组、LPS+抗PD-L1组。记录大鼠体重及病变变化,收获病变组织及重要内脏器官进行检测。并通过免疫组织化学法在人LM组织中检测PD-L1表达情况。结果:PD-L1在大鼠LM模型中有表达,在LPS作用下表达进一步升高;抗PD-L1治疗通过抑制淋巴管内皮细胞增殖和成管不仅对非炎症状态LM有治疗效果,对炎症状态下LM也有显著疗效。与正常皮肤对比,PD-L1在人LM病变中也有表达。结论:PD-L1可能与LM的病理过程密切相关,抗PD-L1治疗为LM的治疗提供新的思路。

Level of circulating PD-L1 expression in patients with advanced gastric cancer and its clinical implications

Objective：The programmed cell death-1 receptor/programmed cell death-1 ligand （PD-1/PD-L1） pathway plays a crucial role in tumor evasion from host immunity.This study was designed to evaluate the association between circulating PD-L1 expression and prognosis in patients with advanced gastric cancer.Methods：Totally 80 advanced gastric cancer patients and 40 health controls from Beijing Cancer Hospital were enrolled in the present study.Circulating PD-L1 expression was tested by enzymelinked immunosorbent assay （ELISA）.The associations between the expression level of PD-L1 and clinicopathological features and prognosis were analyzed statistically.Results：Expression of PD-L1 in advanced gastric cancer patients was significandy up-regulated compared with health people （P=0.006）.The expression of PD-L1 was significantly correlated with differentiation and lymph node metastasis （P=0.026 and P=0.041,respectively）.Although we didn＇t find significant difference in all advanced gastric cancer patients with different PD-L1 expression,the adenocarcinoma patients with higher up-regulated PD-L1 expression had much better prognosis than low expression patients （65.6％ vs.44.7％,P=0.028）.Conclusions：PD-L1 was elevated in advance gastric cancer patients and may play an important role in tumor immune evasion and patients prognosis.

Formalin fixation on HER-2 and PD-L1 expression in gastric cancer:A pilot analysis using the same surgical specimens with different fixation times

BACKGROUND The needs for human epidermal growth factor receptor 2(HER-2) and/or programmed death-ligand 1(PD-L1) evaluations in gastric cancer are dramatically increasing. Although the importance of standardization of sample fixation has been widely recognized, most of the evidence regarding the fixation duration or type of fixing solution are based on breast cancer.AIM To investigate the real effects of fixation conditions on HER-2 testing or PD-L1 testing for gastric cancer using gastrectomy specimens.METHODS Thirty-two patients who underwent gastrectomy for gastric cancer were enrolled.Their resected specimens were each divided into four pieces and fixed in four strictly controlled different durations(6 h, 24 h, and 48 h, and 1 wk) by 10%formalin(n = 22) or 10% neutral buffered formalin(NBF)(n = 10).Immunohistochemistry(IHC) of HER-2 and PD-1 was performed, and a pathology examination was conducted. In the HER-2-immunoreactive cases, all four specimens were subjected to dual-color in situ hybridization(DISH). Five cases were assessed as HER-2-positive by IHC and DISH. We used the cut-off values of 1%, 10%, and 50% to assess the IHC findings of PD-L1.RESULTS No significant difference was observed in comparisons between the shorter fixation period groups(6 h, 24 h, and 48 h) and the prolonged fixation period(1 wk) group in the HER-2 and PD-L1 analyses. Although no significant difference was observed between 10% formalin and 10% NBF within 1 wk of fixation, the superiority of 10% NBF was confirmed in a long-term(> 3 mo) fixation in both the HER-2 and PD-L1 analyses.CONCLUSION In this small-numbered pilot study, prolonged fixation within 1 wk showed no inferiority in HER-2 or PD-L1 testing. However, a large-numbered prospective study is needed to obtain conclusive results.

PD-1/PD-L1 antagonists in gastric cancer:Current studies and perspectives

Immune checkpoints release suppressive signals for T cells,which enable the tumors to escape from immune destruction and provide a new concept that uses the capabilities of the immune system as a therapeutic target for tumors.At present,programmed death receptor 1(PD-1)/programmed death ligand-1(PDL1) has become the most promising therapeutic target.PD-1/PD-L1 blockades exhibit long-lasting antitumor efficacy and safety in patients with various cancers,such as melanoma and non-small-cell lung cancer.Moreover,PD-L1 is highly expressed in the peripheral blood and tumor specimens of patients with cancer,and the expression of PD-L1 is positively correlated with various pathological features and may serve as a predictor of poor prognosis or a diagnostic tool.Clinical trials have verified that PD-1/PD-L1 blockade therapy benefits patients with advanced gastric cancer or gastroesophageal junction cancer.Furthermore,there are many molecules involved in the regulation of PD-1/PD-L1 expression,and the modification of these molecules via drugs and combinations with PD-1/PD-L1 inhibitors may further improve the efficacy of immunotherapy for gastric cancer.In this review,the efficacy,safety,and possible combination treatment options of PD-1/PD-L1 in gastric cancer are reviewed in experimental and clinical settings.

Prognostic significance of PD-L1 expression in patients with colorectal cancer: a meta-analysis

Background The association between the expression of programmed cell death 1(PD-1) or its ligand [programmed cell death ligand-1(PD-L1)] and colorectal cancer(CRC) survival rates remains unclear. Thus, we conducted a meta-analysis to investigate the prognostic value of PD-L1 expression in CRC patients.Methods All eligible studies related to evaluation of PD-L1 expression and survival of CRC patients were searched in PubMed, Medline, Cochrane library, and the EMBASE database. Hazard ratios(HRs) and 95% confidence intervals(CI) of overall survival(OS) were examined to assess the effect of PD-L1 expression on the survival of CRC patients. The outcomes of this meta-analysis were synthesized based on randomeffects model. Subgroup analyses were also performed. Results Seven studies, wherein OS data were stratified according to the expression status of PD-L1, were analyzed. CRC patients showing positive PD-L1 expression were associated with significantly poorer prognoses in terms of overall survival, compared with those displaying negative PD-L1 expression(HR = 1.43, 95% CI: 1.07–1.92; P = 0.02). In the subgroup analyses, H-scores as well as the percentage of stained cells indicated that PD-L1 expression was significantly associated with poor prognosis(HR = 1.90, 95% CI: 1.38–2.62, P < 0.01; HR = 1.81, 95% CI: 1.08–3.03, P = 0.02). Immunohistochemical staining, utilizing a rabbit anti-PD-L1 antibody, revealed significantly superior survival in the PD-L1 negative group compared with the PD-L1 positive expression group(HR = 1.92; 95% CI, 1.40-2.63; P < 0.01). Moreover, PD-L1 expression was significantly associated with poor prognosis when polyclonal antibodies were used(HR = 1.84; 95% CI, 1.30–2.61; P < 0.01). Conclusion Our meta-analysis indicated that PD-L1 expression status is a significant prognostic factor for CRC patients. Positive PD-L1 expression was associated with worse CRC survival. Evaluation via different immunohistochemistry based techniques may partly account for the contradictory results. Therefore, further investigative studies using larger sample sizes are felt to be needed to elucidate the prognostic value of PD-L1 expression in CRC patients.

Bacterial and cancerous cell membrane fused liposome coordinates with PD-L1 inhibitor for cancer immunotherapy

Although tumor cell membranes with broad-spectrum antigens have been explored for cancer vaccines for decades,their relatively poor capacity to stimulate immune responses,especially cellular immune responses,has limited their application.Here,we presented a novel bacterial and cancerous cell membrane fusogenic liposome for co-delivering cell membrane-derived antigens and adjuvants.Meanwhile,a programmed death-ligand 1(PD-L1)inhibitor,JQ-1,was incorporated into the formulation to tackle the up-regulated PD-L1 expression of antigen-presenting cells(APCs)upon vaccination,thereby augmenting its anti-tumor efficacy.The fusogenic liposomes demonstrated significantly improved cellular uptake by APCs and effectively suppressed PD-L1 expression in bone marrow-derived dendritic cells(BMDCs)in vitro.Following subcutaneous vaccination,the nano-vaccines efficiently drained to the tumor-draining lymph nodes(TDLNs),and significantly inhibited PD-L1 expression of both dendritic cells(DCs)and macrophages within the TDLNs and tumors.As a result,the liposomal vaccine induced robust innate and cellular immune responses and inhibited tumor growth in a colorectal carcinoma-burden mouse model.In summary,the fabricated cell membrane-based fusogenic liposomes offer a safe,effective,and easily applicable strategy for tumor immunotherapy and hold potential for personalized cancer immunotherapy.

Effects of Maxingloushi decoction on immune inflammation and programmed death markers in mice with chronic obstructive pulmonary disease

BACKGROUND: To investigate effects of Maxingloushi decoction on lung inflammation and programmed death markers(programmed death-1 [PD-1], programmed death-ligand 1 [PD-L1]) in the lung tissue, peripheral blood, and bronchoalveolar lavage fl uid(BLF) in a mouse model of chronic obstructive pulmonary disease(COPD).METHODS: Thirty-six mature male BALB/C mice were randomly divided into normal group(group A, n=6), COPD model group(group B, n=10), Maxingloushi decoction + COPD group(group C, n=10), and PD-1 inhibitor + COPD group(group D, n=10). The COPD model was established by smoke inhalation combined with lipopolysaccharide(LPS). Levels of PD-1 and PD-L1 in plasma and BLF were measured by enzyme-linked immunosorbent assay(ELISA). Histopathological techniques were used to semi-quantitatively analyze the immuno-fluorescence optical density(IOD) value of the lung tissue. RESULTS: In plasma and BLF, the expression of PD-1 in the group B was higher than that in the group A, and the expression of PD-L1 was lower than that in the group A. The expression of PD-1 and PD-L1 in the lung tissue was normalized in the group C in comparison with the group B(P<0.05) and the group D(P<0.05), and infl ammatory cell infiltration in the lung tissue was also improved.CONCLUSIONS: These findings reveal that COPD causes an immune imbalance in the peripheral blood and lung tissue, and that both Maxingloushi decoction and PD-1 inhibitor treatment can mitigate lung inflammation in COPD by reducing PD-1 expression and increasing PD-L1 expression. The treatment effect of Maxingloushi decoction may be superior to that of PD-1 inhibitor.

Programmed Cell Death-I/Programmed Death-ligand 1 Pathway： A New Target for Sepsis

Objective： Sepsis remains a leading cause of death in many Intensive Care Units worldwide, lmmunosuppression has been a primary locus of sepsis research as a key pathophysiological mechanism. Given the important role of the negative costimulatory molecules programmed cell death-1 （PD-1） and programmed death-ligand 1 （PD-LI） in the occurrence of immunosuppression during sepsis, we reviewed literatures related to the PD-1/PD-L 1 pathway to examine its potential as a new target for sepsis treatment. Data Sources： Studies of the association between PD-I/PD-LI and sepsis published tip to January 31, 2017, were obtained by searching tile PubMed database. Study Selection： English language studies, including those based on animal models, clinical research, and reviews, with data related to PD- 1/PD-L I and sepsis, were evaluated. Results： lmmunomodulatory therapeutics could reverse the deactivation of immune cells caused by sepsis and restore immune cell activation and function. Blockade of＇the PD-1/PD-LI pathway could reduce the exhaustion ofT-cells and enhance the proliferation and activation ofT-cells. Conclusions： The anti-PD- I/PD-L 1 pathway shows promise as a new target for sepsis treatment. This review provides a basis for clinical trials and Iiiture studies aimed at revaluating the efficacy and safety of this targeted approach.

Current and future drug combination strategies based on programmed death-1/programmed death-ligand 1 inhibitors in non-small cell lung cancer

In recent years,immune checkpoint inhibitors(ICIs)have made breakthroughs in the field of lung cancer and have become a focal point for research.Programmed death-1(PD-1)or programmed death-ligand 1(PD-L1)inhibitor monotherapy was the first to break the treatment pattern for non-small cell lung cancer(NSCLC).However,owing to the limited benefit of ICI monotherapy at the population level and its hyper-progressive phenomenon,it may not meet clinical needs.To expand the beneficial range of immunotherapy and improve its efficacy,several research strategies have adopted the use of combination immunotherapy.At present,multiple strategies,such as PD-1/PD-L1 inhibitors combined with chemotherapy,anti-angiogenic therapy,cytotoxic T-lymphocyte-associated protein 4 inhibitors,and radiotherapy,as well as combined treatment with new target drugs,have been evaluated for clinical practice.To further understand the current status and future development direction of immunotherapy,herein,we review the recent progress of ICI combination therapies for NSCLC.

Nuclear Aurora kinase A triggers programmed death-ligand 1-mediated immune suppression by activating MYC transcription in triple-negative breast cancer

Background:Increasing studies have reported that oncogenes regulate components of the immune system,suggesting that this is a mechanism for tumorigenesis.Aurora kinase A(AURKA),a serine/threonine kinase,is involved in cell mitosis and is essential for tumor cell proliferation,metastasis,and drug resistance.However,the mechanism by which AURKA is involved in immune response regulation is unclear.Therefore,this study aimed to investigate the role of AURKA in immune regulation in triple-negative breast cancer(TNBC).Methods:Peripheral blood mononuclear cells(PBMCs)were co-cultured with TNBC cells.The xCELLigence Real-Time Cell Analyzer-MP system was used to detect the killing efficiency of immune cells on TNBC cells.The expression of immune effector molecules was tested by quantitative real-time polymerase chain reaction(qRT-PCR)to evaluate immune function.Furthermore,to validate AURKA-regulated immune response in vivo,4T1 murine breast cancer cell line with AURKA overexpression or downregulation was engrafted into BALB/c mice.The distribution and proportion of immune cells in tumors were further evaluated by immunohistochemistry and flow cytometry.Results:Downregulation of AURKA in TNBC cells increased immune response by activating CD8^(+)T cell proliferation and activity.Nuclear rather than cytoplasmic AURKA-derived programmed death-ligand 1(PD-L1)expression was independent of its kinase activity.Mechanistic investigations showed that nuclear AURKA increased PD-L1 expression via an MYC-dependent pathway.PD-L1 overexpression mostly reversed AURKA silencing-induced expression of immune effector molecules,including interleukin-(IL-2),interferon-γ(IFN-γ),and perforin.Moreover,AURKA expression was negatively correlated with the enrichment and activity of tumor-infiltrating CD8^(+)T cells in 4T1 engrafted BALB/c mouse model.Conclusions:Nuclear AURKA elevated PD-L1 expression via an MYCdependent pathway and contributed to immune evasion in TNBC.Therapies targeting nuclear AURKA may restore immune responses against tumors.

Transarterial chemoembolization in combination with programmed death-1/programmed cell death-ligand 1 immunotherapy for hepatocellular

Hepatocellular carcinoma(HCC)is one of the most common malignancies worldwide.With the development of systemic therapies,several studies are currently underway,especially those related to the use of programmed death-1/programmed cell death-ligand 1(PD-1/PD-L1)immunotherapy.Moreover,studies on transarterial che-moembolization(TACE)and PD-1/PD-L1 immunotherapy have demonstrated some interesting outcomes.This article reviewed the current clinical evidence on the combination of TACE and PD-1/PD-L1 immunotherapy.Overall,our review summarized that a favorable survival time could be achieved using this combination in most patients.However,complications such as hyperprogression should be taken seriously,and the underlying mechanisms need to be explored.

Immune signature of small bowel adenocarcinoma and the role of tumor microenvironment

In this editorial we comment on the article published“Clinical significance of programmed cell death-ligand expression in small bowel adenocarcinoma is determined by the tumor microenvironment”.Small bowel adenocarcinoma(SBA)is a rare gastrointestinal neoplasm and despite the small intestine's significant surface area,SBA accounts for less than 3%of such tumors.Early detection is challenging and the reason arises from its asymptomatic nature,often leading to late-stage discovery and poor prognosis.Treatment involves platinum-based chemotherapy with a 5-fluorouracil combination,but the lack of effective chemotherapy contributes to a generally poor prognosis.SBAs are linked to genetic disorders and risk factors,including chronic inflammatory conditions.The unique characteristics of the small bowel,such as rapid cell renewal and an active immune system,contributes to the rarity of these tumors as well as the high intratumoral infiltration of immune cells is associated with a favorable prognosis.Programmed cell death-ligand 1(PD-L1)expression varies across different cancers,with potential discrepancies in its prognostic value.Microsatellite instability(MSI)in SBA is associated with a high tumor mutational burden,affecting the prognosis and response to immunotherapy.The presence of PD-L1 and programmed cell death 1,along with tumor-infiltrating lymphocytes,plays a crucial role in the complex microenvironment of SBA and contributes to a more favorable prognosis,especially in the context of high MSI tumors.Stromal tumor-infiltrating lymphocytes are identified as independent prognostic indicators and the association between MSI status and a favorable prognosis,emphasizes the importance of evaluating the immune status of tumors for treatment decisions.

Aerosolized immunotherapeutic nanoparticle inhalation potentiates PD-L1 blockade for locally advanced lung cancer

Despite therapeutic advancements,the prognosis of locally advanced non-small cell lung cancer(LANSCLC),which has invaded multiple lobes or the other lung and intrapulmonary lymph nodes,remains poor.The emergence of immunotherapy with immune checkpoint blockade(ICB)is transforming cancer treatment.However,only a fraction of lung cancer patients benefit from ICB.Significant clinical evidence suggests that the proinflammatory tumor microenvironment(TME)and programmed death-ligand 1(PD-L1)expression correlate positively with response to the PD-1/PD-L1 blockade.We report here a liposomal nanoparticle loaded with cyclic dinucleotide and aerosolized(AeroNP-CDN)for inhalation delivery to deep-seated lung tumors and target CDN to activate stimulators of interferon(IFN)genes in macrophages and dendritic cells(DCs).Using a mouse model that recapitulates the clinical LANSCLC,we show that AeroNP-CDN efficiently mitigates the immunosuppressive TME by reprogramming tumor-associated macrophage from the M2 to M1 phenotype,activating DCs for effective tumor antigen presentation and increasing tumor-infiltrating CD8+T cells for adaptive anticancer immunity.Intriguingly,activation of interferons by AeroNP-CDN also led to increased PD-L1 expression in lung tumors,which,however,set a stage for response to anti-PD-L1 treatment.Indeed,anti-PD-L1 antibody-mediated blockade of IFNs-induced immune inhibitory PD-1/PD-L1 signaling further prolonged the survival of the LANSCLC-bearing mice.Importantly,AeroNP-CDN alone or combination immunotherapy was safe without local or systemic immunotoxicity.In conclusion,this study demonstrates a potential nano-immunotherapy strategy for LANSCLC,and mechanistic insights into the evolution of adaptive immune resistance provide a rational combination immunotherapy to overcome it.

Comparison of mismatch repair and immune checkpoint protein profile with histopathological parameters in pancreatic,periampullary/ampullary,and choledochal adenocarcinomas

BACKGROUND Pancreatic,periampullary/ampullary,and choledochal adenocarcinomas are aggressive malignancies with a poor prognosis.Immune checkpoint blockade is a promising treatment option for several tumor types.H long terminal repeatassociating 2(HHLA2),which is analogous to programmed death-ligand 1(PDL1),is a recently discovered member of the B7/cluster of differentiation 28 family and is expressed in many malignancies.AIM To analyze the expression of HHLA2 and its association with the pathologic biomarkers that predict sensitivity to immunotherapy.METHODS Ninety-two adenocarcinoma cases located in the pancreas,ampulla,and distal common bile duct were identified.This study assessed 106 pancreaticoduodenectomy and distal/total pancreatectomy samples that were delivered to Ankara City Hospital between 2019 and 2021.Immunohistochemistry was conducted to examine the expression of DNA mismatch repair(MMR),PD-L1,and HHLA2 proteins.RESULTS Patients with high HHLA2 expression had a higher mean age than those with low expression.Low HHLA2 expression was associated with high perineural invasion.HHLA2 expression was low in pathological stage T3(pT)3 cases and high in pathological stage T1,T2,and T4 cases.There was no correlation between HHLA2 expression and the expression of MMR proteins and PD-L1.CONCLUSION Evaluation of HHLA2 expression in microsatellite stable and PD-L1-negative tumors may be useful for predicting the response of individuals to immunotherapy and may serve as a novel therapeutic target for immunotherapy in advanced-stage disease.