Programmed Death Receptor Ligand Research Articles

Efficacy and influencing factors of immunotherapy combined with chemotherapy and bevacizumab in patients with non-small cell lung cancer after epidermal growth factor receptor tyrosine kinase inhibitors treatment failure

Objective: To investigate the efficacy and influencing factors of immunotherapy combined with chemotherapy and bevacizumab in patients with non-small cell lung cancer (NSCLC) who failed epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. Methods: A retrospective analysis was made on the clinical data of 60 NSCLC patients who were treated with immunotherapy combined with chemotherapy and bevacizumab after EGFR-TKIs treatment failure in the Affiliated Cancer Hospital of Shandong First Medical University from January 2019 to March 2022. Patients were followed up by telephone or outpatient review up to October 1, 2022, with a median follow-up of 8.2 months (95%CI: 7.1-9.3). All 60 patients were followed up. The response evaluation criteria in solid tumors were used to evaluate the short-term efficacy. The adverse reactions of patients were evaluated according to the common terminology criteria for adverse events. The survival curve was drawn by Kaplan-Meier method. Cox proportional hazard regression models were utilized to analyze the influencing factors of progression-free survival (PFS). Results: Among the 60 NSCLC patients, 22 were males. The age ranged from 41 to 75 years, with a median age of 61 years. Eleven patients had partial response, 19 patients had stable disease and 30 patients had progressive disease. The median PFS was 8.2 months (95%CI: 7.2-9.2). The median PFS of patients with low expression of programmed death receptor-ligand 1 (PD-L1) [Tumor cell Proportion Score (TPS)<1%], moderate expression of PD-L1 (1%≤TPS≤49%), and high expression of PD-L1 (TPS≥50%) were 6.4 (95%CI: 4.8-8.0), 8.3 (95%CI: 7.3-9.3) and 10.6 months (95%CI: 7.2-14.1), respectively, and there were statistically significant differences (χ2=13.58, P<0.001). Multivariate Cox proportional risk regression model analysis showed that age>65 years old (HR=4.017, 95%CI: 1.468-10.992, P=0.007) was a risk factor for PFS in NSCLC patients who received immunotherapy combined with chemotherapy and bevacizumab after EGFR-TKIs treatment failure. Moderate expression of PD-L1 (HR=0.360, 95%CI: 0.139-0.930, P=0.035) and high expression of PD-L1 (HR=0.155, 95%CI: 0.039-0.625, P=0.009) were protective factors for PFS. Most of the treatment-related adverse reactions in the whole group were grade 1-2, including bone marrow suppression (n=24), nausea (n=25), decreased appetite (n=24), fatigue (n=22), vomiting (n=18), abnormal liver function (n=17), blood creatinine increased (n=10), and so on. These were tolerated by the patients. Conclusions: NSCLC patients who failed EGFR-TKIs treatment can tolerate adverse reactions related to immunotherapy combined with chemotherapy and bevacizumab treatment. PFS is significantly prolonged in those aged≤65 years and those with moderate and high expression of PD-L1.

Down-regulation of DNA key protein-FEN1 inhibits OSCC growth by affecting immunosuppressive phenotypes via IFN-γ/JAK/STAT-1

Oral squamous cell carcinoma (OSCC) escape from the immune system is mediated through several immunosuppressive phenotypes that are critical to the initiation and progression of tumors. As a hallmark of cancer, DNA damage repair is closely related to changes in the immunophenotypes of tumor cells. Although flap endonuclease-1 (FEN1), a pivotal DNA-related enzyme is involved in DNA base excision repair to maintain the stability of the cell genome, the correlation between FEN1 and tumor immunity has been unexplored. In the current study, by analyzing the clinicopathological characteristics of FEN1, we demonstrated that FEN1 overexpressed and that an inhibitory immune microenvironment was established in OSCC. In addition, we found that downregulating FEN1 inhibited the growth of OSCC tumors. In vitro studies provided evidence that FEN1 knockdown inhibited the biological behaviors of OSCC and caused DNA damage. Performing multiplex immunohistochemistry (mIHC), we directly observed that the acquisition of critical immunosuppressive phenotypes was correlated with the expression of FEN1. More importantly, FEN1 directly or indirectly regulated two typical immunosuppressive phenotype-related proteins human leukocyte antigen (HLA-DR) and programmed death receptor ligand 1 (PD-L1), through the interferon-gamma (IFN-γ)/janus kinase (JAK)/signal transducer and activator transcription 1 (STAT1) pathway. Our study highlights a new perspective on FEN1 action for the first time, providing theoretical evidence that it may be a potential immunotherapy target for OSCC.

Peptide functionalized nanocarriers for targeted drug delivery in cancer therapy.

The intrinsic limitations of conventional cancer therapies have prompted the development of nanocarriers for more effective and safer cancer treatment. Amongst these, nanocarriers functionalized with tumor-targeting moieties have been utilized to enhance delivery of cancer therapeutics. However, recent reports have revealed that only a modest increase in tumor targeting is typically achieved with this approach. Poor tumor accumulation is largely due to formation of a serum protein corona on the surface of the nanocarriers in circulation, which hinders targeting and leads to nonspecific tissue distribution, immune recognition and rapid blood clearance. Here, we present three highly efficient tumor-targeting nanocarriers that overcome the aforementioned issues. These nanocarriers are functionalized with the acidity-triggered rational membrane (ATRAM) peptide that facilitates internalization specifically into cancer cells within the acidic tumor microenvironment. The first system is a hybrid nanocarrier that consists of a drug-loaded polylactic-co-glycolic acid (PLGA) core covalently ‘wrapped’ with a crosslinked bovine serum albumin (BSA) shell. Second are upconversion mesoporous silica nanospheres (UMSNs), with combined photodynamic therapy, photothermal therapy and imaging capabilities, that consist of a lanthanide-doped core ‘wrapped’ with lipid-polyethylene glycol (DSPE-PEG-maleimide). The final system consists of drug-loaded mesoporous silica nanoparticles (MSNs) coated with a lipid bilayer composed of DPPC/Chol/DSPE-PEG-mal. The lipid coat is then functionalized with programmed death receptor ligand-1 antibody (anti-PD-L1 antibody, atezolizumab) to disrupt the programmed death 1 (PD-1) interaction that inhibits the anticancer activity of tumor-infiltrating immune cells. In all three systems, the BSA or lipid coats serve to minimize interactions with serum proteins, which allows the nanocarriers to evade immune recognition and extends the in vivo circulation half-life. All three systems exhibit remarkable tumor-targeting efficiency leading to highly potent anticancer activity, while exhibiting negligible toxicity to healthy tissue. Thus, all three systems represent highly promising nanoplatforms for the targeted delivery of cancer therapeutics.

Expression of neuroendocrine markers predicts increased survival in triple-negative breast cancer patients.

The significance of neuroendocrine (NE) markers in triple-negative breast cancer (TNBC) patients has not been investigated. This study aims to clarify the incidence and prognostic significance of NE marker expression in TNBC, determine its association with other clinicopathological parameters, and further explore the pathological features and potential treatment options for TNBC patients expressing NE markers. Clinicopathological data were collected from 396 TNBC patients undergoing radical breast cancer surgery at Peking Union Medical College Hospital from January 2002 to December 2014, with a final follow-up in July 2019. Immunohistochemistry (IHC) staining was performed for NE markers including chromogranin A (CgA) and synaptophysin (Syn). For TNBC patients with positive NE marker expression, IHC staining was then performed for alpha-thalassemia/mental retardation X-linked (ATRX), O(6)-methylguanine-methyltransferase (MGMT), somatostatin receptor 2 (SSTR2), and programmed death receptor-ligand 1 (PD-L1). The chi-square or Fisher exact test was used to evaluate the correlations between NE marker expression and other parameters. Survival curves were plotted using the Kaplan-Meier (K-M) method to assess the prognostic significance of NE markers in TNBC. NE marker-positive staining was observed in 7.6% (30/396) of all TNBC cases. Only 0.5% (2/396) cases had ≥ 90% neoplastic cells expressing NE markers. Positive NE marker expression was associated with negative basal-like marker expression. K-M survival analysis showed that the NE marker-positive TNBC patients had higher disease-free survival (DFS) rates than the NE marker-negative patients at the same stage. Among the 30 NE marker-positive TNBC cases, 13.3% and 26.7% showed negative IHC staining for ATRX and MGMT, respectively, while 13.3% had a 3+ score for SSTR2 IHC staining. For PD-L1 IHC staining, 13.3% of the 30 TNBC cases were higher than 10 scores in Combined Positive Score (CPS), and 10.0% were higher than 10% in Tumor Cell Proportion Score (TPS). There was a small proportion of TNBC patients expressing NE markers. TNBC patients with positive NE marker expression had a better prognosis than the negative group at the same stage. TNBC cases with positive NE marker expression may potentially benefit from immunotherapy or somatostatin analogue treatment.

Mechanisms and Strategies to Overcome PD-1/PD-L1 Blockade Resistance in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is characterized by a high rate of systemic metastasis, insensitivity to conventional treatment and susceptibility to drug resistance, resulting in a poor patient prognosis. The immune checkpoint inhibitors (ICIs) represented by antibodies of programmed death receptor 1 (PD-1) and programmed death receptor ligand 1 (PD-L1) have provided new therapeutic options for TNBC. However, the efficacy of PD-1/PD-L1 blockade monotherapy is suboptimal immune response, which may be caused by reduced antigen presentation, immunosuppressive tumor microenvironment, interplay with other immune checkpoints and aberrant activation of oncological signaling in tumor cells. Therefore, to improve the sensitivity of TNBC to ICIs, suitable patients are selected based on reliable predictive markers and treated with a combination of ICIs with other therapies such as chemotherapy, radiotherapy, targeted therapy, oncologic virus and neoantigen-based therapies. This review discusses the current mechanisms underlying the resistance of TNBC to PD-1/PD-L1 inhibitors, the potential biomarkers for predicting the efficacy of anti-PD-1/PD-L1 immunotherapy and recent advances in the combination therapies to increase response rates, the depth of remission and the durability of the benefit of TNBC to ICIs.

Expression of nucleus accumbens-1 in colon cancer negatively modulates antitumor immunity.

Nucleus accumbens-1 (NAC-1) is highly expressed in a variety of tumors, including colon cancer, and is closely associated with tumor recurrence, metastasis, and invasion. To determine whether and how NAC-1 affects antitumor immunity in colon cancer. NAC-1-siRNA was transfected into RKO colon cancer cells to knock down NAC expression; tumor cells with or without knockdown of NAC-1 were treated with CD8+ T cells to test their cytocidal effect. The level of the immune checkpoint programmed death receptor-1 ligand (PD-L1) in colon cancer cells with or without knockdown of NAC-1 was analyzed using Quantitative real-time polymerase chain reaction and Western blotting. A double luciferase reporter assay was used to examine the effects of NAC-1 on the transcription of PD-L1. Mice bearing MC-38-OVA colon cancer cells expressing NAC-shRNA or control-shRNA were treated with OT-I mouse CD8+ T cells to determine the tumor response to immunotherapy. Immune cells in the tumor tissues were analyzed using flow cytometry. NAC-1, PD-L1 and CD8+ T cells in colon cancer specimens from patients were examined using immunohistochemistry staining. Knockdown of NAC-1 expression in colon cancer cells significantly enhanced the cytocidal effect of CD8+ T cells in cell culture experiments. The sensitizing effect of NAC-1 knockdown on the antitumor action of cytotoxic CD8+ T cells was recapitulated in a colon cancer xenograft animal model. Furthermore, knockdown of NAC-1 in colon cancer cells decreased the expression of PD-L1 at both the mRNA and protein levels, and this effect could be rescued by transfection of an RNAi-resistant NAC-1 expression plasmid. In a reporter gene assay, transient expression of NAC-1 in colon cancer cells increased the promoter activity of PD-L1, indicating that NAC-1 regulates PD-L1 expression at the transcriptional level. In addition, depletion of tumoral NAC-1 increased the number of CD8+ T cells but decreased the number of suppressive myeloid-derived suppressor cells and regulatory T cells. Tumor expression of NAC-1 is a negative determinant of immunotherapy.

RETRACTED: The heterogeneity of PD-L1 protein in gastric cancer: expression and distribution characteristics

Programmed death receptor ligand 1 (PD-L1) is expressed at different levels in tumour tissues and tumour-infiltrating monocytes (TIMCs). The interpretation of PD-L1 expression in gastric cancer (GC) is more difficult because of its heterogeneity. The PD-L1 immunohistochemistry (IHC) by E1L3N assay was performed in GC tissues. The level and distributed characteristics of PD-L1 expression were observed to illustrate its heterogeneity both in the cancer tissues and TIMCs. The relationship between PD-L1 level and necrotic features of tumor cells, the number of TIMCs, the distribution of tertiary lymphoid tissue (TLS) in the stroma, and other clinicopathological factors were analysed. A Cox regression model was used to assess the prognostic value of PD-L1 expression. Of the 110 GC samples, not only more cases (51/110 cases) could be detected by combined positive score (CPS) for PD-L1 expression compared the other two, tumour positive score (TPS), and mononuclear immune-cell density score (MIDS), but also there were more cases with the high level of PD-L1 expression by CPS, even if with good consistency among them (P < 0.05). The tumour cells with high expression of PD-L1 was prone to show a diffuse distributing, whereas mottled type in the low level. It was noteworthy that the strongly colored tumor cells tended to exhibit a mossy pattern which were distributed along the border between cancer nests and stroma, and the same pattern happened to occur in the positive mesenchymal cells contacting the tumor border, essentially lymphocytes and macrophages. The substantial necrosis in the tumour and the number of TIMCs was analyzed statistically significant correlated with CPS (P < 0.05), while other clinicopathological factors such as histological type, tumour size, invasion depth, TNM stage were uncorrelated. The number and distribution of TLS in the tumour and para-tumoural stroma indirectly affected PD-L1 in GC by associating with the quantity and pattern of TIMCs. Cox regression analysis revealed that the prognosis was poor when PD-L1 was positive. CPS is the best indicator for PD-L1 expression in GC, which tend to be increased expression following a large number of TIMCs and substantial tumour necrosis appeared. Heterogeneity was reflected in the different distributed pattern of PD-L1 expression, especially the mossy-like pantten of the staining tumor cell in the interface between tumour nests and stroma, regardless of the amount and intensity of PD-L1 expression. TLS is valuable for observing microscopic images to influence the quantity and pattern of TIMCs. CPS can be used as an independent prognostic factor for GC.

TP53 Mutation Mapping in Advanced Non-Small Cell Lung Cancer: A Real-World Retrospective Cohort Study.

Background: TP53 is frequently mutated in solid tumors, but its basic mutation mapping is mixed, particularly in aggressive-stage lung cancer. Experimental Design: We curated a total of 139 advanced non-small cell lung cancer (NSCLC) patients who harbored wild-type TP53 (TP53wt) or mutated TP53 (TP53mut) based on next-generation sequencing (NGS) to analyze multiple-dimensional data types, including tumor mutation burden (TMB), programmed death receptor ligand 1 (PD-L1) expression, co-mutant alterations, hotspot mutations distribution, and therapy response. Results: TP53 was evident in 125 mutations and significantly associated with male sex, adenocarcinoma differentiation, smoking history, PD-L1 tumor proportion score, and TMB level. The most frequent mutations were distributed on exon 8, but there were no distinct hotspot mutations. After outlining the co-mutation genes, it is interesting to note that DNA damage repair (DDR) genes were frequent alterations in the mutated TP53 cohort. Even though there was no significant difference between the TP53wt and TP53mut cohorts on therapy response, patients with nucleotide variation in G>T achieved a relatively higher durable clinical benefit (DCB) rate. Conclusions: This real-world retrospective study suggests that molecular stratification on the basis of TP53 mutations should be deeply explored for NSCLC to optimize and modify clinical therapy choices.

Tumor Infiltrating Lymphocyte Expression of PD-1 Predicts Response to Anti-PD-1/PD-L1 Immunotherapy.

Many studies have focused on the role of programmed death receptor ligand 1 (PD-L1) expression in predicting immunotherapy outcomes. Limited clinical data are available regarding the role of programmed death receptor 1 (PD-1; the PD-L1 receptor) expressing tumor-infiltrating lymphocytes (TILs) in PD-1/PD-L1 antibody responsiveness. However, preclinical studies demonstrate that TILs expressing PD-1 contribute to tumor immune evasion. This study analyzed the association between TIL-PD-1 status and outcome after immune checkpoint blockade (ICB) therapy. We evaluated 123 patients with various solid tumors treated with monoclonal antibodies targeting the PD-1/PD-L1 signaling axis. Additionally, 8706 solid tumor specimens were assessed for TIL-PD-1 and tumor mutational burden (TMB) status. The presence of PD-1-expressing TILs in tumors was associated with increased median progression-free survival (7.0 vs 1.9 months; p = 0.006) and overall survival (18.1 vs 8.0 months; p = 0.04) after treatment with ICB. TIL-PD-1-positive patients had an objective response rate (ORR) of 41% (95% CI, 24-61; N = 12/29) compared with 17% (95% CI, 4-43; N = 3/17) for TIL-PD-1-negative patients (p = 0.18). Analyzed as continuous variables, TIL-PD-1 and TMB showed a weak correlation in 8706 solid tumor samples (Pearson r = 0.074); when analyzed as categorical variables (cutoffs: TIL-PD-1 ≥ 1% and TMB ≥ 10 mutations/Mb), the two variables are correlated (p < 0.0001). TIL-PD-1-positive status is also associated with enrichment of pathologic variants within several genes, most notably TP53 (adjusted p < 0.05). TIL-PD-1 positivity in tumors (≥ 1%) is associated with significantly longer progression-free and overall survival after ICB. ClinicalTrials.gov ID: NCT02478931.

Expression of immune checkpoints (PD-L1 and IDO) and tumour-infiltrating lymphocytes in breast cancer

BackgroundBreast cancer (BC) has become the most common cancer globally in 2020 as well as in the United Arab Emirates. The breast tumor microenvironment is composed of various immune cell types, including lymphocytes. Tumour-infiltrating lymphocytes (TILs) play a crucial role in tumor eradication and progression. Further, immune checkpoint markers such as programmed death receptor ligand 1 (PD-L1) and indoleamine-2,3-dioxygenase (IDO) have been associated with tumor evasion from the immune system. In this study, we aimed to explore the status of TILs, PD-L1 and IDO as well as to investigate their association with the clinicopathological parameters. Materials and methodsA total of 59 patients diagnosed with primary infiltrating BC were selected, after which tissue sections were stained to identify TILs along with immunohistochemical staining of PD-L1 and IDO. Moreover, in-silico tools were used to assess the expression of PD-L1, IDO and CD3ε in various molecular subtypes of BC. ResultsIt was found that the percentage of TILs correlated with estrogen receptor (ER) and progesterone receptor (PR) expression. This was supported by the finding that most of the triple-negative breast cancer (TNBC) cases belonged to the group with a high percentage of TILs (h-TILs). Similarly, the expression of PD-L1 and IDO was correlated with the ER and PR, whereas TNBC cases showed a high expression of PD-L1 and IDO. This goes in line with the in-silico findings where the TNBC group showed the highest expression of PD-L1 and IDO as well as the T cell marker CD3ε. ConclusionThis study highlighted a possible link between the immunosuppressive markers PD-L1 and IDO with TILs density in the BC microenvironment.

Potential predictive value of comutant LRP1B and FAT for immune response in non-small cell lung cancer: LRP1B and FAT comutation enhance immune response

BackgroundPreliminary investigation revealed that Low-density lipoprotein receptor-related protein 1b (LRP1B) and FAT atypical cadherin (FAT) family mutation might serve as immune regulators under certain tumor microenvironment. Experimental designWe curated a total of 70 non-small cell lung cancer (NSCLC) patients who harbored alterations in LRP1B and/or FAT family (FAT1/2/3/4) based on next-generation sequencing (NGS) to analyze multiple-dimensional data types, including comutant status, tumor mutation burden (TMB), programmed death receptor ligand 1 (PD-L1) expression, T cell-inflamed gene expression profiling (GEP) and therapy response. Results20 patients with co-occurring mutations in LRP1B and FAT1/2/3/4 revealed a relatively higher TMB level of 17.05 mut/Mb compared with 7.60 mut/Mb and 8.80 mut/Mb in single LRP1B and FAT mutation groups, respectively. LRP1B and FAT members showed specifically enriched T cell-inflamed genes and the co-occurring mutant TP53 status in NSCLC patients who harbor LRP1B/FAT comutations. ConclusionsThis work provides evidence that co-occurring mutations of LRP1B and FAT in NSCLC may serve as a group of potential predictive factors in guiding immunotherapy on the basis of their association with TMB status.

Verification and validation of the anti-PD-L1 antibody, Clone 22C3 on a laboratory-developed test

AimsThe first aim of this study is to compare and validate the performance of the programmed death receptor ligand 1 (PD-L1) IHC 22C3 pharmDx assay kit processed via Dako Omnis...

Synthesis and Biological Evaluation of Small Molecules as Potential Anticancer Multitarget Agents.

Twenty-six triazole-based derivatives were designed for targeting both PD-L1 (programmed death receptor ligand 1) and VEGFR-2 (vascular endothelial growth factor receptor 2). These compounds were synthetized and biologically evaluated as multitarget inhibitors of VEGFR-2, PD-L1 and c-Myc proteins. The antiproliferative activity of these molecules on several tumor cell lines (HT-29, A-549, and MCF-7) and on the non-tumor cell line HEK-293 was determined. The effects on the abovementioned biological targets were evaluated for some selected compounds. Compound 23, bearing a p-chlorophenyl group, showed better results than sorafenib in regard to the downregulation of VEGFR-2 and a similar effect to BMS-8 on both PD-L1 and c-Myc proteins. The antiangiogenic and antivascular activities of chloro derivatives were also established by endothelial microtube formation assay on Matrigel®.

Molecular and clinicopathological analysis revealed an immuno-checkpoint inhibitor as a potential therapeutic target in a subset of high-grade myxofibrosarcoma.

This study aimed to identify differences in genetic alterations between low- and high-grade lesions in myxofibrosarcoma (MFS) and to examine the efficacy of immune checkpoint inhibitors in 45 patients with MFS. First, genetic differences between low- and high-grade components within the same tumor were analyzed in 11 cases using next-generation sequencing. Based on the obtained data, Sanger sequencing was performed for TP53 mutations in the remaining 34 patients. Loss of heterozygosity (LOH) analysis was performed at the TP53 and RB1 loci. Immunohistochemistry was performed for FGFR3, KIT, MET, programmed death receptor ligand 1 (PD-L1), CD8, FOXP3, and mismatch repair proteins. The microsatellite instability status was also evaluated in all cases. TP53 deleterious mutations and LOH at TP53 and RB1 loci were detected significantly more frequently in high-grade than in low-grade MFS (P = 0.0423, 0.0455, and 0.0455, respectively). LOH at the RB1 locus was significantly associated with shorter recurrence-free survival in both univariate and multivariate analyses. TP53 alterations, such as mutation and LOH, were more frequently observed in low-grade areas within high-grade MFS than in pure low-grade MFS. The positive PD-L1 expression rate was 35.6% (16/45), and all these 16 cases were high-grade. A high density of both CD8+ and FOXP3+ tumor-infiltrating lymphocytes was associated with PD-L1 positivity. LOH at the RB1 locus was identified an independent adverse prognostic factor for recurrence-free survival in patients with MFS. Immune checkpoint inhibitors may be a therapeutic option for a subset of high-grade MFS.

Efficacy and Safety of PD-1/PD-L1 Inhibitor Chemotherapy Combined with Lung Cancer Fang No. 1 in Relapsed and Refractory SCLC: A Retrospective Observational Study.

Background Relapsed and refractory small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. The prognosis of patients is poor. The 5-year survival rate is almost 0. The average survival time of patients who refuse to receive treatment is only 2-4 months. For patients with extensive-stage SCLC, the current first-line treatment regimens are mainly platinum-containing double-drug chemotherapy. Poside combined with cisplatin/carboplatin and irinotecan combined with cisplatin/carboplatin are commonly used clinical regimens for the treatment of patients with extensive-stage SCLC. Although SCLC is very sensitive to radiotherapy and chemotherapy, most patients will develop recurrence and metastasis after initial treatment. Therefore, it is necessary to study clinically effective therapeutic drugs for relapsed and refractory SCLC. Objective To investigate the relationship between programmed death receptor-1 (programmed death receptor-1 (PD-1)) and programmed death receptor-ligand 1 (programmed death-ligand 1 (PD-L1)) inhibitors and Lung Cancer No. 1 efficacy and safety of Lung Cancer Fang No. 1 in the treatment of relapsed and refractory SCLC. Methods 80 patients with refractory SCLC were selected and randomly divided into control group and treatment group with 40 cases in each group. Among them, the control group received PD-1/PD-L1 inhibitor chemotherapy, and the treatment group received PD-1/PD-L1 inhibitor chemotherapy combined with Lung Cancer Fang No. 1 treatment. The differences in immune and tumor marker levels, clinical efficacy, and prognostic complications between the two groups before and after treatment were observed and compared. Results Before treatment, there was no significant difference in clinical improvement between the two groups. After treatment, the clinical symptom scores and body weight changes in the treatment group were significantly improved. The clinical symptom scores in the treatment group were lower than those in the control group, but the body weight changes were higher than those in the control group. The difference was statistically significant (P < 0.05). Before treatment, there was no significant difference in the levels of tumor markers between the two groups. After treatment, the levels of CYFRA21-1, CA125, and VGEF in the treatment group were significantly lower than those in the control group, and the difference was statistically significant (P < 0.05). There was no significant difference in the immune level between the two groups before treatment (P > 0.05), while the differences in CD4+, CD3+, and CD4+/CD8+ after treatment were significant, and the treatment group was higher than the control group, with statistical significance (P < 0.05). After treatment, the clinical efficacy of the two groups was significantly improved. The DCR90.00% of the treatment group was significantly higher than that of the control group, 67.50%, and the difference was statistically significant (P < 0.05). The analysis of complications after treatment showed that fatigue, anorexia, hypertension, hand-foot syndrome, diarrhea, leukopenia, thrombocytopenia, and urinary protein in the treatment group were significantly lower than those in the control group, and the difference was statistically significant (P < 0.05). Conclusion PD-1/PD-L1 inhibitor chemotherapy combined with Lung Cancer Fang No. 1 has a good and safe effect on SCLC patients. It has a good curative effect in improving the clinical symptoms of patients. It can stabilize the tumor, inhibit the development of lung cancer, improve the body's cellular immune function, adjust the level and expression of tumor markers, improve the body's material metabolism, and restore the balance of yin and yang in the body.

Tumor targeted mesoporous silica nanoparticles functionalized with programmed death receptor ligand-1 antibody (anti-PD-L1) for combined chemo- and immunotherapy

Traditional chemotherapy is associated with severe side-effects due to non-specific targeting of healthy tissue. An additional drawback of traditional chemotherapy is the development of multidrug resistance (MDR) phenotypes. Here, we overcome these issues by developing a targeted cancer drug delivery nanoplatform that combines immuno- and chemotherapy. We utilize mesoporous silica nanoparticles (MSNs) that are characterized by a high drug loading capacity (within the pores of the nanoparticles) and subsequent controlled drug release (in target cancer cells).

Correlation of PD-L1 expression with toxicities and response in oropharyngeal cancers treated with definitive chemoradiotherapy.

The programmed death receptor ligand 1 (PD-L1) is a cell-surface glycoprotein expressed in tumour cells (TCs) and is also upregulated in tumour infiltrating lymphocytes. The effect of PD-L1 expression on TCs and tumour-infiltrating lymphocytes (TILs) on acute radiation toxicity and response in oropharyngeal squamous cell carcinoma treated with concurrent chemoradiotherapy is less known. Squamous cell carcinoma of oropharynx with stage II-IVA (AJCC 8th) were recruited in this prospective observational study. Definitive radiation therapy (RT) of 70 Gray in 35 fractions at 2 Gray per fraction, 5 fractions a week in 2 phases was delivered with concurrent chemotherapy (cisplatin 40 mg/m2 weekly). Patients were assessed weekly for acute toxicities with Radiation Therapy Oncology Group criteria. Response assessment was done at 3 months post RT according to World Health Organization response assessment criteria. The programmed death receptor ligand 1 expression in TCs and TILs was correlated with acute toxicity and survival. Of 51 patients, 20 (39.2%) had PD-L1 expression in TCs and 18 (35.3%) in TILs. Patients with PD-L1 expression in TCs had fewer grade ≥ 3 oral mucositis (25% vs. 58%; p = 0.02) and grade ≥ 3 dysphagia (25% vs. 55%; p = 0.046). The programmed death receptor ligand 1-tumour infiltrating lymphocytes positives had lower ≥ 3 grade oral mucositis (22% vs. 58%; p = 0.02) and ≥ 3 grade dysphagia (17% vs. 58%; p = 0.007). Two-year overall and progression-free survival rate for the PD-L1-tumour-positive vs. PD-L1-tumour-negative group was not different (p > 0.5). Positive PD-L1 expression is associated with fewer acute radiation toxicities, and this could be used as a potential biomarker.

Overexpression of DAPK1-mediated inhibition of IKKβ/CSN5/PD-L1 axis enhances natural killer cell killing ability and inhibits tumor immune evasion in gastric cancer

Gastric cancer (GC) originates from the stomach and is a prevalent human malignancy. Dysfunction of death associated protein kinase 1 (DAPK1) has been identified as a major regulator involved in the development and progression of GC. However, there’s limited data regarding the regulatory mechanism of GC. Herein, we investigated role of DAPK1 in natural killer (NK) cell killing ability and immune evasion of GC cells and mediated pathway. Samples from GC-related gene expression profile and clinical samples from 67 patients with GC were collected to determine the expression of DAPK1, IκB kinase β (IKKβ), programmed death receptor-ligand 1 (PD-L1), and photomorphogenesis 9 (COP9) signalosome 5 (CSN5). The binding affinity among DAPK1, IKKβ, CSN5, and PD-L1 was characterized to verify the underlying mechanism. GC lines were transfected with overexpressed plasmid or siRNA to determine the effect of DAPK1/IKKβ/CSN5/PD-L1 axis on NK cell killing ability and immune evasion of GC cells. GC cells and tissues presented low expression of DAPK1 and high expression of IKKβ, CSN5 and PD-L1. IKKβ, negatively regulated by DAPK1, was capable of activating CSN5 and upregulating PD-L1 expression. Overexpression of DAPK1 promoted NK cell killing ability and reduced immune evasion, coupled with reduction of NK cell apoptosis and increases in levels of TNF-α, IFN-γ, CD107a, and Granzyme B cytokines. The tumor-suppressing properties of DAPK1 through downregulation of IKKβ/CSN5/PD-L1 axis in GC were further confirmed in vivo. In summary, overexpression of DAPK1 promoted the NK cell killing ability and restrained immune evasion of GC cells, providing a potential therapeutic strategy for GC treatment by modulating immune evasion.

Novel Fluorinated Spermine and Small Molecule PEI to Deliver Anti-PD-L1 and Anti-VEGF siRNA for Highly Efficient Tumor Therapy.

Small interfering RNA (siRNA) can specifically silence disease gene expression. This project investigated the overexpression of programmed death receptor ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF) on the surface of tumor cells. However, the main obstacle to the development of gene therapy drugs is the lack of an efficient delivery vector, which should be able to overcome multiple delivery barriers and protect siRNA to enter the target cells. Therefore, a novel fluorine-modified endogenous molecular carrier TFSPEI was constructed by linking fluorinated groups with hydrophobic and hydrophilic characteristics on the surface of PEI and spermine. The results showed that lower toxicity, higher endocytosis, and silencing efficiency were achieved. We found that the inhibition of VEGF targets can indirectly activate the immune response to promote the tumor-killing and invasion effects of T cells. The combined delivery of anti-VEGF siRNA and anti-PD-L1 siRNA could inhibit the expression of corresponding proteins, restore the anti-tumor function of T cells and inhibit the growth of neovascularization, and obtained significant anti-tumor effects. Therefore, this safe and efficient fluorinated spermine and small molecule PEI-based anti-PD-L1 and anti-VEGF siRNA delivery system is expected to provide a new strategy for gene therapy of tumors.

PD-L1 Status in Gastric Cancers, Association with the Transcriptional, Growth Factors, AKT/mTOR Components Change, and Autophagy Initiation.

Introduction: The programmed death receptor ligand 1 (PD-L1) immunohistochemistry (IHC) assay is a widely used selection method for pembrolizumab treatment in gastric cancer (GC) patients. PD-L1 is the main regulator of immunity in oncogenesis. Material and methods: The study included 38 patients with GC. The combined treatment consisted of neoadjuvant FOLFOX6, or FLOT, chemotherapy and surgery. PD-L1 + tumor status was recorded in 12 patients (CPS > 5), with a negative status recorded in 26 patients. RT-PCR determined the expression of molecular markers. The level of LC3B protein was detected by Western Blotting analysis. Results: An overexpression of PD-1, PD-L2 in the tumor is associated with AKT/mTOR mRNA profile change and autophagy initiation in IHC PD-L1 positive GCs. NACT influences these biological features, modifying the expression of AKT/mTOR components and autophagic flux. In PD-L1 positive cancers, the effect of NACT and molecular markers rearrangements are essential compared to the PD-L1 negative cancers. Conclusion: The IHC PD-L1 status in gastric cancers is the significant marker of cancer progression, recovering the multiple inner mechanisms of cancer spreading and leading to ineffective therapy. Autophagy induction and angiogenesis are found in PD-L1 positive gastric cancers.