Programmed Cell Death Receptor Ligand Research Articles

Immune-related dermatological adverse events of antitumor immunotherapy with PD-1, PD-L1, CTLA-4 inhibitors

The discovery of a new group of modern anticancer drugs was a breakthrough in the treatment of cancer. Immune checkpoint inhibitors that block cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed cell death receptor ligand (PD-L1) may improve prognosis for patients with malignant neoplasms with a high level of microsatellite instability. Despite the high effectiveness of these drugs, immune checkpoint inhibitors can lead to dysregulation of immune responses and the occurrence of adverse reactions associated with an increase in the activity of immunocompetent cells in the body. The aim of this review is to analyze the available data on the immune-related dermatological adverse events during treatment with immune checkpoint inhibitors.

Programmed cell death-ligand 2: new insights in cancer.

Immunotherapy has revolutionized cancer treatment, with the anti-PD-1/PD-L1 axis therapy demonstrating significant clinical efficacy across various tumor types. However, it should be noted that this therapy is not universally effective for all PD-L1-positive patients, highlighting the need to expedite research on the second ligand of PD-1, known as Programmed Cell Death Receptor Ligand 2 (PD-L2). As an immune checkpoint molecule, PD-L2 was reported to be associated with patient's prognosis and plays a pivotal role in cancer cell immune escape. An in-depth understanding of the regulatory process of PD-L2 expression may stratify patients to benefit from anti-PD-1 immunotherapy. Our review focuses on exploring PD-L2 expression in different tumors, its correlation with prognosis, regulatory factors, and the interplay between PD-L2 and tumor treatment, which may provide a notable avenue in developing immune combination therapy and improving the clinical efficacy of anti-PD-1 therapies.

Early Molecular Steps in Human Bone Marrow Stem Cell Differentiation Trajectories

Understanding the molecular signatures of human hematopoietic stem/progenitor cells (HSCPs) and gene network changes leading to differentiation induction are of utmost importance to achieve therapeutic hematopoietic stem cell (HSC) expansion. The identification of surface markers has improved the prospective isolation of human bone marrow HSCs over the last decades, but the isolated population still remains very heterogeneous. Single cell sequencing approaches have the potential to unbiased assort stem cells along their differentiation stages and trajectories, and to decipher molecular markers in differentiation hierarchies. However, whole transcriptome single cell sequencing often suffers from inadequate detection of low-expressed genes with increased drop-outs. To address this limitation and to provide sensitive mRNA quantification in human HSPCs, we developed a selected targeted gene panel (600 genes) in combination with 50 protein markers to cover most relevant genes/proteins of early HSPC differentiation and cell cycle status. We employed single cell CITE-Seq (cellular indexing of transcriptomes and epitopes by sequencing) based multi-omic profiling to >60.000 high-quality FACS-enriched human bone marrow HSPCs (CD34 + and CD34 +CD38 - cells) from 15 healthy donors representing young, mid and old age groups. Here, we demonstrate the most comprehensive molecular map of early human HSC differentiation and provide evidence of early branching points into lineage trajectories across different age groups using Slingshot pseudotime analysis. Our data demonstrate that the HSC branched into two main lineages, with the first branching point giving rise to megakaryocytic and erythroid progenitors (MKP/ERP), followed by lymphoid and myeloid progenitors (LMP/MDP). As expected, the most immature HSCs were defined by high expression of CD34, CD90, CRHBP, HOPX, HLF, MLLT3. However, we observed a number of hitherto undescribed HSC markers. The MKP/ERP lineage was defined by GATA1, TFRC, CD36, MPL and VWF expression. Furthermore, we found CD274, the Programmed Cell Death receptor ligand 1, to be selectively expressed in the MKP cluster. Re-clustering and trajectory analysis of the most immature CD34 +CD38 -/low cells confirmed early lineage commitment, suggesting that an MKP/ERP development does not include myeloid or lymphoid progenitors. A similar pattern was observed for all age groups. Interestingly, we observed increased expression of novel marker genes ( HLA-E, DLK1, ADGRG6, ADGRG1, MMRN1) and proteins (CD137 and CD273) in the most immature HSCs. Besides a gradual upregulation of CD38 along differentiation, differentiated cells showed lower CD45 levels. Furthermore, MKP/ERP committed cells showed a downregulation of SPINK2. TradeSeq analysis defined the continuous single cell expression changes in genes and markers upon early differentiation and lineage commitment, allowing the detection of decision-making gene networks. Our data adds further evidence to the revised model of hematopoiesis that challenges the dogma of a common myeloid progenitor giving rise to erythroid, megakaryocytic and myeloid cells. Furthermore, we see a structured hierarchical organization with a sequential loss of lineage potential and not an early commitment of uni-lineage restricted precursors. We report on the upregulation of ADGRG6, ADGRG1, DLK1, HLA-E, MMRN1 CD137 and CD273 in the most immature HSCs. Molecular and functional characterization of CD273 hi and low HSCs are presented in an adjacent report by our group at this meeting (Schmachtel et al.). In conclusion, we provide a valuable resource for the continuous regulation of genes and surface proteins along early differentiation of very immature human HSCs.

Circular RNA circ_0101675 Promotes NSCLC Cell Proliferation, Migration, Invasion, Angiogenesis and Immune Evasion by Sponging miR-607/PDL1 Axis.

Non-small cell lung cancer (NSCLC) is one of the most common and fatal cancers in the world. Circular RNA (circRNA) can broadly participate in the initiation and progression of the NSCLC. However, the regulatory mechanisms of circRNA in NSCLC remain poorly understood. In present study, we aimed to explore the potential role of circ_0101675 in the progression of NSCLC.Quantitative real-time polymerase chain reaction was performed to examine the expression of circ_0101675, microRNA-607 (miR-607) and programmed cell death receptor ligand 1 (PDL1) in NSCLC tissues and cells. Cell count kit 8 assay, colony formation assay, wound healing assay, transwell assay, tube formation assay and flow cytometry were applied to examine NSCLC cell proliferation, migration, invasion, angiogenesis and apoptosis. NSCLC cells were co-cultured with peripheral blood mononuclear cells to assess immune response. The protein levels of PDL1 and proteins related to apoptosis were detected by western blotting. Dual-luciferase reporter assay and RNA immunoprecipitation assay were conducted to verify the direct target site between miR-607 and circ_0101675 or PDL1. The experiments in vivo were employed to explore the effects of circ_0101675 on tumor growth in NSCLC.Circ_0101675 and PDL1 were high-expressed, while miR-607 was low-expressed in NSCLC cells and cancer tissues. The suppression of circ_0101675 suppressed growth, migration, invasion, angiogenesis and immune escape in NSCLC cells. Mechanistically, we found that high level of circ_0101675 could upregulate PDL1 expression via sponging miR-607. Moreover, the down-regulation of circ_0101675 inhibited the growth of NSCLC tumors in vivo by enhancing miR-607 expression to decrease PDL1 expression.Taken together, our results suggested that circ_0101675 might promote the proliferation, migration, invasion, and immune evasion abilities of NSCLC through miR-607/PDL1 axis.

PD-L1 and tumor-infiltrating CD8+ lymphocytes are correlated with clinical characteristics in pediatric and adolescent pituitary adenomas.

To investigate the levels of tumor-infiltrating CD8+ lymphocytes (CD8+ TILs) and the expression of programmed cell death receptor ligand 1 (PD-L1) in the tumor microenvironment (TME) of pediatric and adolescent pituitary adenomas (PAPAs) and analyze the correlation between their levels and the clinical characteristics. A series of 43 PAPAs cases were enrolled over a period of 5 years. To compare the TME of PAPAs and adult PAs, 43 PAPAs cases were matched with 60 adult PAs cases (30 cases were between 20 and 40 years old, and 30 cases were older than 40 years) for main clinical characteristics. The expression of immune markers in PAPAs was detected by immunohistochemistry, and their correlation with the clinical outcomes was analyzed using statistical methods. In the PAPAs group, CD8+ TILs level was significantly lower (3.4 (5.7) vs. 6.1 (8.5), p = 0.001), and PD-L1 expression (0.040 (0.022) vs. 0.024 (0.024), p < 0.0001) was significantly higher as compared with the older group. The level of CD8+ TILs was negatively correlated with the expression of PD-L1 (r = -0.312, p = 0.042). Moreover, CD8+ TILs and PD-L1 levels were associated with Hardy (CD8, p = 0.014; PD-L1, p = 0.018) and Knosp (CD8, p = 0.02; PD-L1, p = 0.017) classification. CD8+ TILs level was associated with high-risk adenomas (p = 0.015), and it was associated with the recurrence of PAPAs (HR = 0.047, 95% CI 0.003-0.632, p = 0.021). Compared with the TME in adult PAs, the TME in PAPAs was found to express a significantly altered level of CD8+ TILs and PD-L1. In PAPAs, CD8+ TILs and PD-L1 levels were associated with clinical characteristics.

Bioactive compounds derived from marine source: a potential immunotherapy treatment

Immunotherapy using checkpoint inhibitors blocks the checkpoint proteins (programmed cell death receptor-1; PD-1) from binding with their corresponding ligands (programmed cell death receptor ligand-1; PD-L1) to regulate cell signaling pathways. The marine environment holds a huge source of small molecules that are understudied which can be developed as an inhibitor. Hence, this study investigated the inhibitory effect of 19 algae-derived small molecules against PD-L1 by using molecular docking, absorption, distribution, metabolism, and elimination (ADME) properties and molecular dynamics simulations (MDS). The molecular docking revealed that the binding energy of the six best compounds ranges from −11.1 to −9.1 kcal/mol. Fucoxanthinol, in particular, has the strongest binding energy at −11.1 kcal/mol with three hydrogen bonds (ASN:63A, GLN:66A, and ASP:122A). Meanwhile, the MDS demonstrated that the ligands were strongly bound to the protein, indicating the stability of the complexes. In summary, the identified compounds are potential PD-L1 inhibitors in immunotherapy. Communicated by Ramaswamy H. Sarma

Changes in PD-L1 and tumor mutational burden between paired samples and relationship to immune checkpoint inhibitor outcomes in non-small cell lung cancer.

9127 Background: Programmed cell death receptor ligand 1 (PD-L1) tumor proportion score (TPS) and tumor mutational burden (TMB) are key biomarkers of response to immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC). How often PD-L1 and TMB values change across samples within individual patients (pts) and the impact of this variation on ICI outcomes are limited. Methods: Pts with NSCLC and multiple PD-L1 or TMB assessments at the Dana-Farber Cancer Institute were included. Clinicopathologic and genomic data were analyzed in association with PD-L1 and TMB changes. In patients with &gt; 2 samples, each sample was paired with the subsequent and each pair was analyzed independently. Minor and major changes in PD-L1 were defined as absolute changes of 10-49% and 50-100%, respectively. Results: The PD-L1 cohort included 402 sample pairs (median ΔPD-L1: 0; range: -90,+95%) and the TMB cohort included 413 sample pairs (median ΔTMB: 0 mut/Mb; range: -20.6,+24.5). Concordance between pairs was high for both PD-L1 ( R= 0.53, P &lt; 0.01) and TMB ( R= 0.80, P &lt; 0.01). Samples taken within &lt; 1 year had higher concordance for PD-L1 than samples taken ≥1 year apart (P &lt; 0.01), but length of time between biopsies did not impact TMB concordance. Minor or no changes in PD-L1 were observed in 82.3% of pairs; the frequency of major increases was 9.7% and major decreases was 8%. After dividing TMB into tertiles, 72.6% sample pairs showed no tertile change, 16% increased to a higher tertile, and 11.4% decreased to a lower tertile. PD-L1, but not TMB, decreased with intervening ICI (P = 0.02), but PD-L1 and TMB did not change significantly with other intervening systemic therapies. Acquired copy number losses of the CD274 gene (encoding for PD-L1) were enriched in pairs with a major PD-L1 decrease (Q &lt; 0.05). Similarly, acquired loss of chromosome 9p (which contains the CD274 locus) correlated with a reduction in PD-L1, while 9p gains correlated with an increase in PD-L1 (P = 0.02). A total of 142 pts had multiple PD-L1 scores assessed before ICI initiation. Among pts with at least one PD-L1-positive sample (TPS ≥1%), the presence of another sample that was PD-L1 negative ( &lt; 1%) correlated with worse outcomes to ICI compared to pts with no PD-L1-negative samples: response rate was 11% vs 39% (P &lt; 0.01), median progression-free survival (mPFS) 2.7 vs 8.0 months (P &lt; 0.01), and median overall survival 13.6 vs 21.2 months (P = 0.05), respectively. Among pts with at least one PD-L1 TPS ≥1% and one &lt; 1%, cases where the last PD-L1 TPS before ICI was ≥1% achieved longer mPFS than if the pre-ICI sample was PD-L1 negative (3.6 vs 1.8 months, P = 0.03). Conclusions: Although PD-L1 and TMB generally had high intrapatient concordance across samples, significant changes in values occurred in some patients. Variations in PD-L1 influenced ICI outcomes, warranting an assessment proximal to ICI initiation whenever feasible.

Circ_0058058 Drives the Malignant Phenotypes and Immune Evasion of Pancreatic Cancer by the MicroRNA-557-Dependent Regulation of PDL1.

Pancreatic cancer (PC) is one of the most deadly malignancies in the world. Recently, circular RNAs play crucial roles in PC progression. However, the functions of circ_0058058 in PC are barely known. The expression of circ_0058058, microRNA-557-5p (miR-557), and programmed cell death receptor ligand 1 (PDL1) was detected by quantitative real-time polymerase chain reaction. Functional experiments were implemented to disclose the effect of circ_0058058 deficiency on PC cell proliferation, apoptosis, invasion, angiogenesis, and immune escape. The binding relationship between miR-557 and circ_0058058 or PDL1 was identified by dual-luciferase reporter assay and RNA immunoprecipitation assay. In vivo assay was used to disclose the impact of circ_0058058 silencing on tumor formation in vivo. Circ_0058058 was highly expressed in PC tissues and cell lines. Knockdown of circ_0058058 repressed cell proliferation, invasion, angiogenesis, and immune escape while contributed to apoptosis in PC cells. Mechanically, circ_0058058 worked as a molecular sponge of miR-557 to regulate PDL1 expression. Moreover, circ_0058058 showed a promotional effect on tumor growth in vivo. Our findings suggested that circ_0058058 served as miR-557 sponge to upregulate PDL1, thereby triggering PC proliferation, invasion, angiogenesis, and immune escape.

Cost-effectiveness analysis of adjuvant therapy with atezolizumab in Chinese patients with stage IB-IIIA resectable NSCLC after adjuvant chemotherapy.

BackgroundAtezolizumab was first shown to significantly improve progression-free survival (PFS) after platinum-based chemotherapy in early-stage non-small cell lung cancer (NSCLC) in the IMpower010 Phase 3 trial. However, the cost-effectiveness and potential economic impact of atezolizumab treatment in Chinese patients are unknown.MethodsMarkov models were constructed based on follow-up data from the IMpower010 trial and assessed separately in the programmed cell death receptor ligand-1 (PD-L1) tumor cells (TC) ≥ 1% stage II – IIIA group, all stage II – IIIA groups, and the intention-to-treat (ITT) group (stage IB–IIIA). Efficacy and safety data were obtained from the IMpower010 trial, and costs and utility values were derived from the literature and local surveys to estimate their incremental cost-effectiveness ratios (ICERs) compared with willingness-to-pay (WTP) thresholds in scenarios implementing patient assistance programs (PAP) or drug price negotiations. Univariate sensitivity analysis and probabilistic sensitivity analysis (PSA) were performed to investigate the stability of the model results.ResultsCompared with best supportive care (BSC), atezolizumab produced an additional 0.45 quality-adjusted life-years (QALYs), 0.04 QALYs, and -0.0028 QALYs in the PD-L1 TC ≥ 1% stage II – IIIA group, all stage II – IIIA groups, and the ITT group, and the ICERs were 108,825.37/QALY, 1,028,538.22/QALY, and -14,381,171.55/QALY, respectively. The ICERs all exceeded the WTP threshold of $27,354 per QALY (three times the per capita gross domestic product of China in 2022), and univariate sensitivity analysis showed that the price of atezolizumab played a crucial role in the model results. PSA showed that the probability of cost-effectiveness of atezolizumab in the PD-L1 TC ≥ 1% stage II – IIIA group, all stage II – IIIA groups, and the ITT group increased with the increasing WTP threshold.ConclusionFrom the perspective of China’s health care system, in the PD-L1 TC ≥ 1% stage II – IIIA group, all stage II – IIIA groups, and the ITT group, the use of atezolizumab in the adjuvant treatment of patients with early-stage NSCLC after platinum-based chemotherapy is unlikely to be cost-effective. The implementation of PAP or price reduction negotiations for atezolizumab might be among the most effective measures to improve its cost-effectiveness.

Prognostic and predictive biomarkers with therapeutic targets in breast cancer: A 2022 update on current developments, evidence, and recommendations.

To evaluate and validate the recent and emerging data for prognostic and predictive biomarkers with therapeutic targets in breast cancer. A literature search from January 2015 to March 2022 was performed using the key terms breast cancer, clinical practice guidelines, gene mutations, genomic assay, immune cancer therapy, predictive and/or prognostic biomarkers, and targeted therapies. Relevant clinical trials, meta-analyses, seminal articles, and published evidence- and consensus-based clinical practice guidelines in the English language were identified, reviewed and evaluated. Breast cancer is a biologically heterogeneous disease, leading to wide variability in treatment responses and survival outcomes. Biomarkers for breast cancer are evolving from traditional biomarkers in immunohistochemistry (IHC) such as estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor type 2 (HER2) to genetic biomarkers with therapeutic implications (e.g. breast cancer susceptibility gene 1/2 [BRCA1/2], estrogen receptor α [ESR1] gene mutation, HER2 gene mutation, microsatellite instability [MSI], phosphatidylinositol 3-kinase catalytic subunit 3Cα [PIK3CA] gene mutation, neurotrophic tyrosine receptor kinase [NTRK] gene mutation). In addition, current data are most robust for biomarkers in immunotherapy (e.g. programmed cell death receptor ligand-1 [PD-L1], microsatellite instability-high [MSI-H] or deficient mismatch repair [dMMR]). Oncotype DX assay remains the best validated gene expression assay that is both predictive and prognostic whereas MammaPrint is prognostic for genomic risk. Biomarker-driven therapies have the potential to confer greater therapeutic advantages than standard-of-care therapies. The purported survival benefits associated with biomarker-driven therapies should be weighed against their potential harms.

Population Pharmacokinetics of Nivolumab in Japanese Patients with Nonsmall Cell Lung Cancer.

Nivolumab is an antiprogrammed death-1 (PD-1) antibody used for immuno-oncological therapy of various cancers, including nonsmall cell lung cancer (NSCLC). This study aimed to characterize the real-world population pharmacokinetics (PK) of nivolumab in patients with NSCLC. PK samples were collected by opportunistic sampling of Japanese patients with NSCLC treated with nivolumab monotherapy. Population PK analysis was performed using a two-compartment model in Nonlinear Mixed Effect Model. Patient-specific factors such as body weight, age, sex, serum albumin, estimated glomerular filtration rate, performance status, programmed cell death receptor ligand 1 expression in tumors, and treatment periods were evaluated as potential covariates for clearance. A total of 223 serum samples collected from 34 patients were available for analysis. The median (min-max) age and weight were 69 years (38-83 years) and 62.7 kg (36.8-80.5 kg), respectively. The mean (95% confidence interval) clearance estimate was 0.0064 L/h (0.0058-0.0070 L/h). The inclusion of the ALB level, estimated glomerular filtration rate, and treatment period significantly improved the model fit. A real-world nivolumab population PK model was developed using an opportunistic sampling strategy in Japanese patients with NSCLC. Further studies are warranted to characterize the exposure-response relationship and determine the optimal dosing regimens for these patients.

Molecular mechanism of lncRNA SNHG12 in immune escape of non-small cell lung cancer through the HuR/PD-L1/USP8 axis

BackgroundThe pivotal role of long noncoding RNAs (lncRNAs) in cancer immune responses has been well established. This study was conducted with the aim of exploring the molecular mechanism of lncRNA small nucleolar RNA host gene 12 (SNHG12) in immune escape of non-small cell lung cancer (NSCLC).MethodsExpression of lncRNA SNHG12, programmed cell death receptor ligand 1 (PD-L1), ubiquitin-specific protease 8 (USP8), and human antigen R (HuR) in NSCLC tissues and cells was measured, and their binding relationship was determined. NSCLC cell proliferation and apoptosis were assessed. Peripheral blood mononuclear cells (PBMCs) were co-cultured with NSCLC cells. The ratio of CD8+ T cells, PBMC proliferation, and inflammatory factors were determined. lncRNA SNHG12 localization was assessed via subcellular fractionation assay. The half-life period of mRNA was determined using actinomycin D. Xenograft tumor models were established to confirm the role of lncRNA SNHG12 in vivo.ResultsLncRNA SNHG12 was found to be prominently expressed in NSCLC tissues and cells, which was associated with a poor prognosis. Silencing lncRNA SNHG12 resulted in the reduction in proliferation and the promotion of apoptosis of NSCLC cells, while simultaneously increasing PBMC proliferation and the ratio of CD8+ T cells. Mechanically, the binding of lncRNA SNHG12 to HuR improved mRNA stability and expression of PD-L1 and USP8, and USP8-mediated deubiquitination stabilized the protein level of PD-L1. Overexpression of USP8 or PD-L1 weakened the inhibition of silencing lncRNA SNHG12 on the immune escape of NSCLC. Silencing lncRNA SNHG12 restricted tumor growth and upregulated the ratio of CD8+ T cells by decreasing USP8 and PD-L1.ConclusionLncRNA SNHG12 facilitated the immune escape of NSCLC by binding to HuR and increasing PD-L1 and USP8 levels.

Anti-tumor immunity and ferroptosis of hepatocellular carcinoma are enhanced by combined therapy of sorafenib and delivering modified GO-based PD-L1 siRNAs.

Programmed cell death receptor ligand 1 (PD-L1)/PD-1 signaling has been exploited to design inhibitors that deliver promising clinical outcome albeit with limited efficacy. Herein, we prepare graphene oxide (GO)-PEI-PEG with low cytotoxicity and long stability and GO-PEI-PEG delivers PD-L1 siRNAs to hepatocellular carcinoma (HCC) cells by the endocytosis-lysosome pathway. The functional GO-PEI-PEG/PD-L1 siRNAs decrease PD-L1 and PD-1 abundance, increase pro-inflammation cytokine IFN-γ and TNF-α release, and improve the proliferation activity of Jurkat T cells. Since GO-PEI-PEG targets the mouse liver effectively, the intrahepatic tumors in C57BL/6 mice are treated with GO-PEI-PEG/Pd-l1 siRNAs via the tail vein, resulting in shrinkage of the HCC tumors and boosting the anti-tumor efficacy in combination with oral sorafenib. A single treatment improves the total CD3+ and cytotoxic CD8+ T cell infiltration in the HCC tumor tissues and even spleen and upregulates the expression of Perforin, Gzmb, Ifng, Il-1b and Tnfa in the tumors after the combined treatment. Both the single and combined treatments enhance reactive oxygen species (ROS) accumulation, and improved HCC ferroptosis. The results suggest that GO-PEI-PEG delivered PD-L1 siRNAs combined with oral sorafenib can activate the adaptive immunity and tumor ferroptosis and reveal an effective therapy to treat advanced HCC patients.

First-line Cemiplimab versus Standard Chemotherapy in Advanced Non-small Cell Lung Cancer Patients with at Least 50% Programmed Cell Death Receptor Ligand-1 Positivity: Analysis of Cost-effectiveness

AimsThe EMPOWER-Lung 1 trial showed that cemiplimab significantly prolongs the duration of progression-free survival and overall survival in advanced non-small cell lung cancer (NSCLC) patients with at least 50% programmed cell death receptor ligand-1 (PD-L1) positivity, yet the financial burden may limit its use. The aim of the present study was to evaluate the cost-effectiveness of cemiplimab versus chemotherapy in a US setting. Materials and methodsA Markov model, with three mutually exclusive health states, was used to compare the expected health outcomes and cost of cemiplimab with chemotherapy. Survival data and transition probabilities were collected from the EMPOWER-Lung 1 trial. Utility values and costs are publicly available from open sources. One-way and probabilistic sensitivity analyses were conducted in both the whole population and subgroups to test the robustness of the parameters and structure. ResultsTreatment of NSCLC with cemiplimab yielded an extra 1.07 quality-adjusted life years (QALYs) at an additional cost of $98 211 compared with chemotherapy, associated with an incremental cost-effectiveness ratio of $91 891/QALY and an incremental net health benefit of 0.087 QALYs at a willingness to pay threshold of $100 000/QALY. The probabilistic sensitivity analysis indicated that cemiplimab provided an 83.2% probability of being cost-effective. One-way sensitivity analysis suggested that the price of cemiplimab was the chief driver in this model. A subgroup analysis showed that cemiplimab was the preferred incremental net health benefit in more than half of the subgroups, including patients with squamous type disease and metastases. ConclusionsCemiplimab is a cost-effective option in the first-line treatment of NSCLC in patients who are at least 50% PD-L1 positive from an American perspective.

PD-L1 expression, EGFR and KRAS mutations and survival among stage III unresected non-small cell lung cancer patients: a Danish cohort study

Programmed cell death receptor ligand-1 (PD-L1) expression, KRAS (KRASm) and EGFR (EGFRm) mutations may influence non-small cell lung cancer (NSCLC) prognosis. We aimed to evaluate PD-L1 expression, KRASm, and EGFRm and survival among stage III unresected NSCLC patients. Using Danish registries, we collected data on stage III unresected NSCLC patients diagnosed 2001–2012 and paraffin-embedded tumor tissue from pathology archives. We assessed PD-L1 expression in tumors and tumor-infiltrating immune cells (ICs) by immunohistochemistry (ge 1% threshold for PD-L1+). We genotyped KRAS and EGFR. Follow-up extended from 120 days post-diagnosis to death, emigration, or 31/12/2014. We computed median survival using Kaplan–Meier methods, and hazard ratios (HRs) using Cox regression associating the biomarkers with death, adjusting for confounders. Among 305 patients, 48% had adenocarcinoma; 38% squamous cell carcinoma. Forty-nine percent had PD-L1+ tumors—51% stage IIIA and 26% KRASm. Few (2%) patients had EGFRm. Median survival in months was 14.7 (95% CI = 11.8–17.9) and 13.4 (95% CI = 9.5–16.3) in PD-L1+ and PD-L1− tumors, respectively. KRASm was not associated with death (HR = 1.06, 95% CI = 0.74–1.51 versus wildtype). PD-L1+ tumors yielded a HR = 0.83 (95% CI = 0.63–1.10); PD-L1+ ICs a HR = 0.51 (95% CI = 0.39–0.68). Tumor expression of PD-L1 did not influence survival. PD-L1+ ICs may confer survival benefit in stage III unresected NSCLC patients.

The benefits and risks of CTLA4 inhibitor plus PD1/PDL1 inhibitor in stage IIIB/IV non-small cell lung cancer: A systematic analysis and meta-analysis based on randomized controlled trials.

Although immune checkpoint inhibitors (ICIs) have shown clinical benefit for patients with non-small cell lung cancer (NSCLC), the efficacy of the combination of ICIs targeting different pathways is still unclear. We performed this meta-analysis to explore the efficacy of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor plus programmed cell death 1 receptor (PD-1)/programmed cell death receptor ligand 1 (PD-L1) inhibitor therapy (CP) for NSCLC IIIB/IV patients. We systematically searched the main databases for relevant studies. The main outcomes were overall survival (OS) and progression-free survival (PFS). We identified 3526 articles, including 5 randomized controlled trials (RCTs) (4377 patients), in our meta-analysis. We conducted two comparisons of CP versus chemotherapy or PD1/PDL1 inhibitor (P). Compared with chemotherapy, CP was more effective, with better OS (hazard ratio [HR]: 0.77, 95% CI [confidence interval]: 0.66-0.91; p=0.001), better PFS (HR: 0.77, 95% CI: 0.70-0.85; p<0.00001) and comparable objective response rate (ORR) (risk ratio [RR]: 1.27, 95% CI: 0.98-1.65; p=0.07); in terms of toxicity, CP was comparable to chemotherapy across all-grade adverse events (AEs) (RR: 0.87, 95% CI: 0.73-1.03; p=0.11) and grade 3-5 AEs (RR: 0.85, 95% CI: 0.63-1.14; p=0.27). Compared with P, CP had no superiority in efficacy in terms of the OS (HR: 1.04, 95%CI: 0.86-1.24; p=0.70), PFS (HR: 0.95, 95%CI: 0.75-1.22; p=0.70) and the ORR (RR: 1.07, 95% CI: 0.95-1.21; p=0.27) but CP was more effective than P when PD-L1 expression was <1% (RR: 0.77,95%CI: 0.60-0.98; p=0.04); in terms of toxicity, CP was associated with increased all-grade AEs (RR:1.07, 95% CI: 0.97-1.19; p=0.18) and grade 3-5 AEs (RR:1.58, 95% CI: 1.21-2.07; p=0.0008). CP is a beneficial therapeutic schedule with longer PFS and OS than chemotherapy and has an acceptable, manageable grade 3-4 AE rate in IIIB/IV NSCLC. However, compared with P, CP results in better OS only in patients with PD-L1 expression <1%.

Circ-Keratin 6c Promotes Malignant Progression and Immune Evasion of Colorectal Cancer through microRNA-485-3p/Programmed Cell Death Receptor Ligand 1 Axis.

Recently, circular RNA was reported to be a significant participant in the development of tumorigenesis, including colorectal cancer. Therefore, we aimed to clarify the precise role of circ-keratin 6C (circ-KRT6C) in colorectal cancer progression. The relative expression levels of circ-KRT6C, microRNA-485-3p (miR-485-3p), and programmed cell death receptor ligand 1 (PDL1) were analyzed by real-time quantitative polymerase chain reaction and Western blot assays. The proliferation was assessed by cell count kit 8 and colony-forming assays. The apoptotic cells were determined by flow cytometry assay. The migration and invasion were analyzed by transwell assay. Colorectal cancer cells were cocultured with peripheral blood mononuclear cells or cytokine-induced killer cells to assess immune response. The interaction relationships among circ-KRT6C, miR-485-3p, and PDL1 were examined by dual-luciferase reporter assay. The effects of circ-KRT6C inhibition in vivo were analyzed by an animal experiment. circ-KRT6C was overexpressed in colorectal cancer tissues and cells, and its level was associated with overall survival time of patients with colorectal cancer. The suppression of circ-KRT6C suppressed growth, migration, invasion, and immune escape while stimulating apoptosis in colorectal cancer cells, which was abolished by shortage of miR-485-3p. In addition, overexpression of miR-485-3p repressed malignant progression and immune evasion of colorectal cancer by targeting PDL1, implying that PDL1 was a functional target of miR-485-3p. A xenograft experiment also suggested that circ-KRT6C inhibition could repress tumor growth in vivo. circ-KRT6C could increase PDL1 expression by functioning as an miR-485-3p sponge, which promoted malignant progression and immune evasion of colorectal cancer cells. SIGNIFICANCE STATEMENT: circ-keratin 6c could increase programmed cell death receptor ligand 1 expression by functioning as a microRNA-16-5p sponge, which promoted malignant progression and immune evasion of colorectal cancer.

A205 PEMBROLIZUMAB ASSOCIATED SCLEROSING CHOLANGITIS RESPONDS TO COMBINATION OF STEROIDS AND MYCOPHENOLIC ACID: A CASE REPORT

Abstract Background Pembrolizumab is a check point inhibitor that targets programmed cell death receptor ligand 1 (PD-L1). However, check-point inhibitors are associated with its characteristic adverse event know as immune related adverse events that can affect a myriad of organ systems. In the hepatobiliary system, the most commonly described iRAE is hepatitis/hepatotoxicity and latest oncology guidelines offer recommendations on treatment and followup of immunotherapy related hepatitis (1). However, a more rare presentation of iRAE, that have only been described as case reports or case series, is secondary cholangitis. We report one of such a case. Aims Case report Methods Case report Results The patient is a 55 year-old Caucasian female know for lung adenocarcinoma presented to the emergency room on May 5th, 2020, having received her 8th cycle of pembrolizumab. Her blood works mildly elevated transaminitis; ALT 78 U/L, AST 11 U/L, alkaline phosphate of 130 U/L, and total bilirubin of 3.5 umol/L. MRI of the abdomen showed a normal appearing liver without focal parenchymal lesion, no biliary stones or obstructing masses, dilated common bile duct at 11 mm with small pericholecystic free fluid, and normal gall badder thickness of 2 mm. There was also notion of minimally prominent intrahepatic biliary radicles seen within the CBD. Etiology workup of cholestatic transaminitis was negative. A diagnosis of immunotherapy related sclerosing cholangitis was posed and the patient was treated with MMF and prednisone with good response. Conclusions Discussion This patient seems to have developed immunotherapy mediated cholangitis. Liver biopsy when performed in liver injury tend to show lobular hepatitis, with liver parenchyma infiltrated with lymphocytes and focal necrosis with acidophilic bodies. However, there seems to be another, less frequent pattern of injury described with pembrolizumab and associated with cholangiopathy, resembling primary biliary cholangitis. It is characterized with portal tracts enlarged with fibrosis and inflammatory cells infiltration; infiltrating cells are lymphocytes (2). Biliary epithelium with fibrosis with CD8+ T cells infiltration seem to be recurrently reported in case reports. (3, 4). Other cases have been describe in the literature. In many cases, steroid therapy was attempted, but response rates seem to be inconsistent. Nivolumab related cholangitis have been also been described and characterized by extra hepatic bile duct dilatation along with negative immunological markers such as ANA and IgG4 in patients with non-small cell lung cancer, and seems to respond only moderately to steroid therapy (6). Retrospective data of nivolumab related cholangiopathy seems to suggest that there is favourable response to the combination of MMF and steroid therapy (7). Funding Agencies None

Ongoing Evaluation of Immune-related Response Assessment in Brain Metastases

脑转移瘤是成人恶性神经系统肿瘤最常见的病因。针对这一部分人群，治疗手段有限，预后不佳。近年来，以程序性死亡受体1（programmed cell death protein 1, PD-1）及程序性死亡受体配体1（programmed cell death protein ligand 1, PD-L1）抑制剂为主的免疫治疗，给恶性肿瘤的治疗模式带来了革新。免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）彻底改变了晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）的治疗模式。ICI在某些驱动基因阴性的NSCLC脑转移瘤治疗中，取得了令人鼓舞的结果。然而，针对脑转移瘤患者的临床研究，不仅相应的临床数据有限，其疗效的评价也缺乏统一标准。本文旨在阐述不同的疗效评价标准及其在临床研究中的应用，比较之间的异同，并对未来发展趋势进行展望。

MicroRNA-142-5p Suppresses Proliferation and Invasion of Non-Small Cell Lung Cancer Cells by Targeting Programmed Cell Death Receptor Ligand 1

Lung cancer is one of the most deadly tumor disease in the world and most lung cancer is non-small cell lung cancer. MicroRNAs are considered as a variety of endogenous non-coding RNA, acting as interference during the process after transcription of gene. Recently, microRNA-142-5p, one of the microRNAs, was reported to enhance anti-tumor immune of non-small cell lung cancer cells by targeting programmed cell death receptor ligand 1. Programmed cell death receptor ligand 1 was also believed to be a regulator of cell proliferation and migration. However, the effect of microRNA-142-5p on proliferation and invasion of non-small cell lung cancer cells via regulating programmed cell death receptor ligand 1 was still unknown. Thus, this study demonstrated that there was low expression level of microRNA-142-5p in different nonsmall cell lung cancer cell lines. Programmed cell death receptor ligand 1 was proved to be the target gene of microRNA-142-5p and microRNA-142-5p also had negative correlation with programmed cell death receptor ligand 1. The high expression of microRNA-142-5p lead to suppression of proliferation and invasion in non-small cell lung cancer cells by down regulation of programmed cell death receptor ligand 1. The mechanism of microRNA-142-5p affecting proliferation and invasion of non-small cell lung cancer cells via targeting programmed cell death receptor ligand 1 might give a new thought of tumor therapy.