BACKGROUND/AIM: Cemiplimab in patients with non-small cell lung cancer (NSCLC) with PD-L1 (programmed death ligand type 1) expression ≥50% showed a significant improved overall survival (OS) with increasing expression of PD-L1. To our knowledge there exist no similar data published for pembrolizumab regarding the increased OS in relation to the PD-L1 expression. Therefore, the objective of our study was to determine whether improvement in OS reflects increased expression levels of PD-L1 (≥50%) in patients with NSCLC. PATIENTS AND METHODS: Retrospective data from 9 Czech and 1 Polish comprehensive oncology Centers were used. All patients with stage IV NSCLC and PD-L1 expression ≥50% treated with pembrolizumab in daily practice were included. The groups of patients according to the expression of PD-L1 were determined as follows: PD-L1 50-59%, 60-69%, 70-79%, 80-89% and 90-100%. The log-rank test and the Cox regression model were used to compare survival between study groups. RESULTS: A total of 617 patients were included in the study. We did not observe a statistically significant difference in OS between groups of patients with different levels of PD-L1 expression in the pooled comparison (p=0.445). Furthermore, we did not observe a statistically significant difference even when comparing OS in patients with PD-L1expression of 50-59% (reference) with the group of other patients according to the level of expression of PD-L1 in the Cox regression model including the effect covariates. CONCLUSION: PD-L1 expression showed no significant effect on OS in patients with NSCLC with PD-L1≥50% treated with pembrolizumab.
- MeSH
- antigeny CD274 * metabolismus genetika MeSH
- dospělí MeSH
- humanizované monoklonální protilátky * terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové biomarkery metabolismus MeSH
- nádory plic * farmakoterapie mortalita metabolismus patologie genetika MeSH
- nemalobuněčný karcinom plic * farmakoterapie mortalita metabolismus patologie genetika MeSH
- prognóza MeSH
- protinádorové látky imunologicky aktivní terapeutické užití MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- staging nádorů MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Despite extensive research, the molecular role of AGR2 in the progression and metastasis of colorectal cancer (CRC) has not been fully characterized. We used quantitative mass spectrometry (SWATH MS) to identify differentially expressed proteins in paired CRC cell models of the SW480 and SW620 cell lines in response to AGR2 protein level manipulation. Relying on the results from SWATH MS and subsequent immunochemical validation, we selected NMP3 as the top candidate protein associated with AGR2 in CRC tumour cells in our screen. RT‒qPCR and immunochemical analysis confirmed the involvement of AGR2-mediated regulation of NPM3 at the transcriptional and posttranscriptional levels. Since PD-L1 is a constituent of the NPM3 regulatory axis, we aimed to correlate the changes in PD-L1 to the differential expression of AGR2 in our cell models. We found that AGR2 positively regulates PD-L1 levels in both SW480 and SW620 cell lines; additionally, several different CRC patient transcriptome cohorts confirmed the association of AGR2 with PD-L1. Our work reveals a new AGR2-NPM3 regulatory axis and the involvement of AGR2 in the regulation of PD-L1, which paves the way for the association of AGR2 with immune evasion in CRC cells.
- MeSH
- antigeny CD274 * metabolismus genetika MeSH
- jaderné proteiny metabolismus genetika MeSH
- kolorektální nádory * genetika metabolismus patologie MeSH
- lidé MeSH
- mukoproteiny * metabolismus genetika MeSH
- nádorové buněčné linie MeSH
- nukleofosmin * MeSH
- onkogenní proteiny * metabolismus genetika MeSH
- proteiny * metabolismus genetika MeSH
- regulace genové exprese u nádorů * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
PD-L1 is one of the two programmed cell death 1 (PD-1) ligands and a part of an immune checkpoint system (PD-1/PD-L1) with widespread clinical application. The aim of this study was to investigate PD-L1 expression and its association with clinicopathological and prognostic significance in non-clear cell renal cell carcinoma (non-ccRCC) patients. A total of 41 papillary (pRCC) and 20 chromophobe (chRCC) RCC tumors were examined for PD-L1 expression by immunohistochemistry in the cancer cells and tumor-infiltrating mononuclear cells (TIMCs). PD-L1 positivity was detected in 36.6% pRCC and 85.0% chRCC cancer cells, while PD-L1 positivity was observed in 73.2% pRCC and 50.0% chRCC TIMCs. PD-L1 positivity in both pRCC and chRCC tumor cells was not correlated with any of the examined clinicopathological features, while PD-L1 positivity in TIMCs was associated with the age of patients with pRCC. During follow-up, the death was documented among 6 patients with pRCC. Papillary RCC patients with PD-L1-positive tumor cells were significantly associated with an increased risk of death compared with patients with PD-L1-negative cancer cells. A similar trend was observed when comparing PD-L1 expression in TIMCs. However, no differences in overall survival for PD-L1-positive pRCC patients with compared to PD-L1-negative patients were observed in tumor cells or TIMCs.
- MeSH
- antigeny CD274 genetika MeSH
- antigeny CD279 MeSH
- karcinom z renálních buněk * genetika MeSH
- leukocyty MeSH
- lidé MeSH
- nádory ledvin * genetika MeSH
- transkripční faktory MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: In the CASPIAN trial, first-line durvalumab plus platinum-etoposide (EP) significantly improved overall survival (OS) versus EP alone in extensive-stage small cell lung cancer (ES-SCLC). We report exploratory analyses of CASPIAN outcomes by programmed cell death ligand-1 (PD-L1) expression and tissue tumor mutational burden (tTMB). EXPERIMENTAL DESIGN: Patients were randomized (1:1:1) to durvalumab (1,500 mg) plus EP, durvalumab plus tremelimumab (75 mg) plus EP, or EP alone. Treatment effects in PD-L1 and tTMB subgroups were estimated using an unstratified Cox proportional hazards model. RESULTS: The PD-L1 and tTMB biomarker-evaluable populations (BEP) comprised 54.4% (438/805) and 35.2% (283/805) of the intention-to-treat population, respectively. PD-L1 prevalence was low: 5.7%, 25.8%, and 28.3% had PD-L1 expression on ≥1% tumor cells (TC), ≥1% immune cells (IC), and ≥1% TCs or ICs, respectively. OS benefit with durvalumab plus EP versus EP was similar across PD-L1 subgroups, with HRs all falling within the 95% confidence interval (CI) for the PD-L1 BEP (0.47‒0.79). OS benefit with durvalumab plus tremelimumab plus EP versus EP was greater in PD-L1 ≥1% versus <1% subgroups, although CIs overlapped. There was no evidence of an interaction between tTMB and treatment effect on OS (durvalumab plus EP vs. EP, P = 0.916; durvalumab plus tremelimumab plus EP vs. EP, P = 0.672). CONCLUSIONS: OS benefit with first-line durvalumab plus EP in patients with ES-SCLC was observed regardless of PD-L1 or tTMB status. PD-L1 expression may prove to be a useful biomarker for combined treatment with PD-(L)1 and CTLA-4 inhibition, although this requires confirmation with an independent dataset. See related commentary by Rolfo and Russo, p. 652.
- MeSH
- antigeny CD274 genetika MeSH
- etoposid MeSH
- humanizované monoklonální protilátky * MeSH
- lidé MeSH
- malobuněčný karcinom plic * farmakoterapie genetika MeSH
- monoklonální protilátky * MeSH
- nádory plic * farmakoterapie genetika MeSH
- platina MeSH
- protokoly protinádorové kombinované chemoterapie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
BACKGROUND/AIM: Classic Hodgkin lymphoma (cHL) is a common B-cell malignancy. Despite the good prognosis, in some patients the standard chemotherapy and radiotherapy-based approach does not lead to long-term remission, and these patients eventually relapse. Moreover, the primary refractory disease is of major concern regarding prognosis. PATIENTS AND METHODS: We performed a retrospective analysis to evaluate PD-L1 expression in 120 patients with classic Hodgkin lymphoma (cHL). RESULTS: The median follow-up of the entire group of patients was 90 months. After initial therapy, complete remission was achieved in 113 (94.2%) patients. During the follow-up, cHL relapse/refractory disease was reported in 23 (19.2%) cases. A total of five patients died during the follow-up period, all from cHL progression. When determining PD-L1 expression on Hodgkin-Reed-Sternberg (HRS) cells, 37 cases (30.8%) were evaluated as negative, and 83 cases (69.2%) as positive. In the negative PD-L1 group of patients, no cHL relapse/refractory disease was observed during the follow-up period. However, out of 83 patients with positive PD-L1 expression on HRS cells, 23 (28%) showed relapse/refractory cHL. CONCLUSION: A significantly higher relapse rate was observed in PD-L1-positive patients diagnosed with cHL.
Colorectal carcinoma (CRC) is a disease that causes significant morbidity and mortality worldwide. To improve treatment, new biomarkers are needed to allow better patient risk stratification in terms of prognosis. This study aimed to clarify the prognostic significance of colonic-specific transcription factor special AT-rich sequence-binding protein 2 (SATB2), cytoskeletal protein cytokeratin 7 (CK7), and immune checkpoint molecule programmed death-ligand 1 (PD-L1). We analyzed a cohort of 285 patients with surgically treated CRC for quantitative associations among the three markers and five traditional prognostic indicators (i.e., tumor stage, histological grade, variant morphology, laterality, and mismatch-repair/MMR status). The results showed that loss of SATB2 expression had significant negative prognostic implications relative to overall survival (OS) and cancer-specific survival (CSS), significantly shortened 5 years OS and CSS and 10 years CSS in patients with CRC expressing CK7, and borderline insignificantly shortened OS in patients with PD-L1 + CRC. PD-L1 showed a significant negative impact in cases with strong expression (membranous staining in 50-100% of tumor cells). Loss of SATB2 was associated with CK7 expression, advanced tumor stage, mucinous or signet ring cell morphology, high grade, right-sided localization but was borderline insignificant relative to PD-L1 expression. CK7 expression was associated with high grade and SATB2 loss. Additionally, a separate analysis of 248 neoadjuvant therapy-naïve cases was performed with mostly similar results. The loss of SATB2 and CK7 expression were significant negative predictors in the multivariate analysis adjusted for associated parameters and patient age. In summary, loss of SATB2 expression and gain of CK7 and strong PD-L1 expression characterize an aggressive phenotype of CRC.
- MeSH
- antigeny CD274 genetika metabolismus MeSH
- keratin-7 genetika MeSH
- kolorektální nádory * patologie MeSH
- lidé MeSH
- nádorové biomarkery metabolismus MeSH
- prognóza MeSH
- transkripční faktory genetika MeSH
- vazebné proteiny DNA v oblastech připojení k matrix * genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The immune system is important for elimination of residual leukemic cells during acute myeloid leukemia (AML) therapy. Anti-leukemia immune response can be inhibited by various mechanisms leading to immune evasion and disease relapse. Selected markers of immune escape were analyzed on AML cells from leukapheresis at diagnosis (N = 53). Hierarchical clustering of AML immunophenotypes yielded distinct genetic clusters. In the absence of DNMT3A mutation, NPM1 mutation was associated with decreased HLA expression and low levels of other markers (CLIP, PD-L1, TIM-3). Analysis of an independent cohort confirmed decreased levels of HLA transcripts in patients with NPM1 mutation. Samples with combined NPM1 and DNMT3A mutations had high CLIP surface amount suggesting reduced antigen presentation. TIM-3 transcript correlated not only with TIM-3 surface protein but also with CLIP and PD-L1. In our cohort, high levels of TIM-3/PD-L1/CLIP were associated with lower survival. Our results suggest that AML genotype is related to blast immunophenotype, and that high TIM-3 transcript levels in AML blasts could be a marker of immune escape. Cellular pathways regulating resistance to the immune system might contribute to the predicted response to standard therapy of patients in specific AML subgroups and should be targeted to improve AML treatment.
- MeSH
- akutní myeloidní leukemie * diagnóza genetika MeSH
- antigeny CD274 genetika MeSH
- biologické markery MeSH
- buněčný receptor 2 viru hepatitidy A genetika MeSH
- DNA methyltransferasa 3A * genetika MeSH
- lidé MeSH
- mutace MeSH
- nukleofosmin * genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- antigeny CD274 genetika účinky léků MeSH
- karcinom z přechodných buněk * farmakoterapie patologie MeSH
- kritéria léčebné odpovědi MeSH
- lidé MeSH
- nivolumab terapeutické užití MeSH
- protinádorové látky imunologicky aktivní terapeutické užití MeSH
- regulace genové exprese u nádorů genetika účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- komentáře MeSH
- souhrny MeSH
COVID-19, caused by SARS-CoV-2 virus, emerged as a pandemic disease posing a severe threat to global health. To date, sporadic studies have demonstrated that innate immune mechanisms, specifically neutrophilia, NETosis, and neutrophil-associated cytokine responses, are involved in COVID-19 pathogenesis; however, our understanding of the exact nature of this aspect of host-pathogen interaction is limited. Here, we present a detailed dissection of the features and functional profiles of neutrophils, dendritic cells, and monocytes in COVID-19. We portray the crucial role of neutrophils as drivers of hyperinflammation associated with COVID-19 disease via the shift towards their immature forms, enhanced degranulation, cytokine production, and augmented interferon responses. We demonstrate the impaired functionality of COVID-19 dendritic cells and monocytes, particularly their low expression of maturation markers, increased PD-L1 levels, and their inability to upregulate phenotype upon stimulation. In summary, our work highlights important data that prompt further research, as therapeutic targeting of neutrophils and their associated products may hold the potential to reduce the severity of COVID-19.
- MeSH
- antigeny CD274 genetika metabolismus MeSH
- COVID-19 MeSH
- cytokiny genetika metabolismus MeSH
- dendritické buňky imunologie MeSH
- dospělí MeSH
- imunofenotypizace MeSH
- koronavirové infekce krev imunologie MeSH
- kultivované buňky MeSH
- lidé středního věku MeSH
- lidé MeSH
- monocyty imunologie MeSH
- neutrofily imunologie MeSH
- pandemie MeSH
- přirozená imunita MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- virová pneumonie krev imunologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Background: The links between the p53/MDM2 pathway and the expression of pro-oncogenic immune inhibitory receptors in tumor cells are undefined. In this report, we evaluate whether there is p53 and/or MDM2 dependence in the expression of two key immune receptors, CD276 and PD-L1. Methods: Proximity ligation assays were used to quantify protein-protein interactions in situ in response to Nutlin-3. A panel of p53-null melanoma cells was created using CRISPR-Cas9 guide RNA mediated genetic ablation. Flow cytometric analyses were used to assess the impact of TP53 or ATG5 gene ablation, as well as the effects of Nutlin-3 and an ATM inhibitor on cell surface PD-L1 and CD276. Targeted siRNA was used to deplete CD276 to assess changes in cell cycle parameters by flow cytometry. A T-cell proliferation assay was used to assess activity of CD4+ T-cells as a function of ATG5 genotype. Results: CD276 forms protein-protein interactions with MDM2 in response to Nutlin-3, similar to the known MDM2 interactors p53 and HSP70. Isogenic HCT116 p53-wt/null cancer cells demonstrated that CD276 is induced on the cell surface by Nutlin-3 in a p53-dependent manner. PD-L1 was also unexpectedly induced by Nutlin-3, but PD-L1 does not bind MDM2. The ATM inhibitor KU55993 reduced the levels of PD-L1 under conditions where Nutlin-3 induces PD-L1, indicating that MDM2 and ATM have opposing effects on PD-L1 steady-state levels. PD-L1 is also up-regulated in response to genetic ablation of TP53 in A375 melanoma cell clones under conditions in which CD276 remains unaffected. A549 cells with a deletion in the ATG5 gene up-regulated only PD-L1, further indicating that PD-L1 and CD276 are under distinct genetic control. Conclusion: Genetic inactivation of TP53, or the use of the MDM2 ligand Nutlin-3, alters the expression of the immune blockade receptors PD-L1 and CD276. The biological function of elevated CD276 is to promote altered cell cycle progression in response to Nutlin-3, whilst the major effect of elevated PD-L1 is T-cell suppression. These data indicate that TP53 gene status, ATM and MDM2 influence PD-L1 and CD276 paralogs on the cell surface. These data have implications for the use of drugs that target the p53 pathway as modifiers of immune checkpoint receptor expression.
- MeSH
- antigeny B7 genetika MeSH
- antigeny CD274 genetika MeSH
- buněčný cyklus účinky léků genetika MeSH
- buňky A549 MeSH
- HCT116 buňky MeSH
- imidazoly farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- melanom farmakoterapie MeSH
- nádorové buněčné linie MeSH
- nádorový supresorový protein p53 genetika MeSH
- piperaziny farmakologie MeSH
- proliferace buněk účinky léků genetika MeSH
- protoonkogenní proteiny c-mdm2 genetika MeSH
- upregulace účinky léků genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
