Browsing by Subject "PD-L1"
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- PublicationOpen AccessBATF is involved in the malignant phenotype and epithelial-mesenchymal transition of colon cancer cells via ERK/PD-L1 signaling(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Chen, Xiaoqiong; Dong, Huaqian; Jin, LipingObjective. Transcription factors have emerged as primary regulators in colon cancer. Basic Leucine Zipper Transcription Factor (BATF) was found to be differentially expressed in colon cancer. This study aimed to explore the impact of BATF on the malignant phenotype and epithelial-mesenchymal transition (EMT) process. Methods. Based on The Cancer Genome Atlas (TCGA) data, the correlation between BATF and patients’ overall prognosis was analyzed. BATF expression in epithelial and colon cancer cells was evaluated. By knocking down its levels in colon cancer cells, its effects on the malignant phenotype, apoptosis, EMT progression, and ERK/PD-L1 were evaluated. Cells were treated with ERK/PD-L1 agonists, and the BATF cell regulation was re-examined. Results. BATF levels were negatively correlated with patients’ overall survival. BATF is upregulated in colon cancer cell lines, and BATF knockdown in HCT116 cells suppressed the malignant cellular phenotypes (proliferation, migration, and invasion) and increased apoptosis. BATF knockdown inhibited EMT and ERK/PD-L1 signaling activation, whereas upon agonist treatment, BATF potency was disrupted. Conclusion. This study revealed that BATF is involved in the malignant phenotype and EMT of colon cancer cells, and this process may be mediated by ERK/PD-L1 signaling
- PublicationOpen AccessPD-L1 positive lympho-epithelial lesions in inflammatory prostate(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2022) Dikov, Dorian; Koleva, Maria; Simitchiev, Kiril; Baltov, Marin; Sarafian, VictoriaObjectives. Ductal epithelial changes (lympho-epithelial lesions-LEL) in prostatic chronic inflammation (CI) are not well studied so far. Aim. To investigate LEL immediately adjacent to prostatic CI. Methods. We studied LEL in 144 prostatic surgical and autopsy specimens in various types of prostatic CI: NIH-category IV prostatitis (histologic prostatitis-HP), nonspecific granulomatous prostatitis (NSGP), and the reactive lymphoid infiltrates in the vicinity of benign prostatic hyperplasia (BPH) and prostate adenocarcinoma (PCa). CI is scored as low and high grade (LG, HG) according to the severity of inflammation. Results. LEL was identified in all types of prostatic specimens and in all types of prostatic CI: in 70.9% of patients with HP; in 100% of cases with NSGP; in 68.7% and in 80% adjacent to BPH and PCa respectively. Statistical analysis showed a significant correlation of the presence of LEL with HG CI (p<0.001). LEL showed strong membranous PD-L1 expression. Conclusions. The study presents the first attempt to examine LEL in inflammatory human prostate. PD-L1 positive LEL have no diagnostic organ specificity, although they are a constant histological finding in HG prostatic CI. LEL, inducible after birth by CI, are an integral part of prostate-associated lymphoid tissue (PALT) and of the inflammatory prostatic microenvironment
- PublicationEmbargoPembrolizumab plus eribulin in hormone-receptor–positive, HER2-negative, locally recurrent or metastatic breast cancer (KELLY): An open-label, multicentre, single-arm, phase Ⅱ trial(Elsevier, 2021-05) PérezGarcía, José M.; Llombart-Cussac, Antonio; Gion, María; Curigliano, Giuseppe; López Miranda, Elena; Alonso Romero, José Luis; Bermejo, Begoña; Calvo, Lourdes; Carañana, Vicente; Cruz Sánchez, Susana de la; Márquez Vázquez, Raúl; Prat, Aleix; Ruiz Borrego, Manuel; Sampayo Cordero, Miguel; Seguí-Palmer, Miguel Á.; Soberino, Jesús; Malfettone, Andrea; Schmid, Peter; Cortés, Javier; MedicinaBackground Pembrolizumab has modest activity if used in patients with hormone-receptor–positive (HR+), HER2-negative, previously treated metastatic breast cancer (BC). Our study investigated whether there would be any clinical benefit in combining chemotherapy with pembrolizumab in a similar patient population. Methods This single-arm, phase Ⅱ trial enrolled women aged ≥18 years with HR+, HER2-negative, inoperable, locally recurrent or metastatic BC. Patients were previously treated with hormonal therapy and 1–2 chemotherapy regimens for locally recurrent and/or metastatic BC. On each 21-day cycle, patients received intravenous pembrolizumab 200 mg on day 1 and eribulin 1∙23 mg/m2 on days 1 and 8. The primary endpoint was the clinical benefit rate. Analysis of safety and activity was carried out in all patients who met the screening criteria and received at least 1 dose of study treatment. The trial is registered at ClinicalTrials.gov, NCT03222856. Results Of the 44 patients enrolled between January 29 and October 17, 2018, clinical benefit was achieved in 25 (56∙8%, 95% confidence interval [CI]: 41∙0–71∙7), objective response in 18 (40∙9%, 95% CI: 26∙3–56∙8), median progression-free survival was 6∙0 months (95% CI: 3∙7–8∙4), and 1-year overall survival was 59∙1% (95% CI: 45∙8–76∙2). The most common treatment-emergent adverse events (AEs) of any grade were neutropenia (20 [45∙5%]), anaemia (17 [38∙6%]), alopecia (19 [43∙2%]), asthenia (19 [43∙2%]), diarrhoea (14 [31∙8%]), fatigue (14 [31∙8%]), and peripheral neuropathy (12 [27∙3%]). Serious AEs occurred in 14 (31∙8%) patients including febrile neutropenia (3 [6∙8%]), neutropenia (2 [4∙5%]), fever (2 [4∙5%]) and peripheral neuropathy (2 [4∙5%]). Immune-related AEs occurred in 11 (25∙0%) patients. One (2∙3%) patient died of cardiac arrest unrelated to study treatment. Conclusion Pembrolizumab plus eribulin demonstrates encouraging antitumour activity in patients with heavily pre-treated, HR+, HER2-negative, locally recurrent or metastatic BC. The safety and tolerability of the combination is similar to eribulin or pembrolizumab monotherapy.
- PublicationOpen AccessPembrolizumab plus gemcitabine in the subset of triple-negative advanced breast cancer patients in the GEICAM/2015-04 (PANGEA-Breast) study(MDPI, 2021-10-29) Cruz-Merino, Luis de la; Gion, María; Cruz-Jurado, Josefina; Quiroga, Vanesa; Andrés, Raquel; Moreno, Fernando; Alonso-Romero, José Luis; Ramos, Manuel; Holgado, Esther; Cortés, Javier; López-Miranda, Elena; Henao-Carrasco, Fernando; Palazón-Carrión, Natalia; Rodríguez, Luz M.; Ceballos, Isaac; Casas, Maribel; Benito, Sara; Chiesa, Massimo; Bezares, Susana; Caballero, Rosalia; Jiménez-Cortegana, Carlos; Sánchez-Margalet, Víctor; Rojo, Federico; MedicinaThe PANGEA-Breast trial evaluated a new chemo-immunotherapeutic combination that would synergistically induce long-term clinical benefit in HER2-negative advanced breast cancer patients. Treatment consisted of 21-day cycles of 200 mg of pembrolizumab (day 1) plus gemcitabine (days 1 and 8). The primary objective was the objective response rate (ORR). The tumor infiltrating lymphocytes (TILs) density and PD-L1 expression in tumor, and the myeloid-derived suppressor cells (MDSCs) level in peripheral blood, were analyzed to explore associations with treatment efficacy. Considering a two-stage Simon’s design, the study recruitment was stopped after its first stage as statistical assumptions were not met. A subset of 21 triple-negative breast cancer (TNBC) patients was enrolled. Their median age was 49 years; 15 patients had visceral involvement, and 16 had ≤3 metastatic locations. Treatment discontinuation due to progressive disease (PD) was reported in 16 patients. ORR was 15% (95% CI 3.2–37.9). Four patients were on treatment >6 months before PD. Grade ≥3 treatment-related adverse events were observed in 8 patients, where neutropenia was the most common. No association was found between TILs density, PD-L1 expression or MDSCs levels and treatment efficacy. ORR in TNBC patients also did not meet the assumptions, but 20% were on treatment >6 months.
- PublicationOpen AccessThe immune microenvironment of cancer of the uterine cervix(Universidad de Murcia. Departamento de Biología Celular e Histología, 2024) Mastrogeorgiou, Michail; Chatzikalil, Elena; Theocharis, Stamatios; Papoudou-Bai, Alexandra; Péoc’h, Michel; Mobarki, Mousa; Karpathiou, GeorgiaWhile several treatment choices exist for cervical cancer, such as surgical therapy, chemotherapy, and radiotherapy, some patients will still show poor prognosis. HPV infection is a principal factor for cervical cancer development, from early inflammation to proliferation, angiogenesis, and neoplastic growth. While HPV T-cell responses exist, the tumor seems to evade the immune system upon its tolerance. The latter suggests the existence of a confluent tumor microenvironment responsible for the evasion tactics employed by the neoplasm. Therefore, novel biomarkers governing prognosis and treatment planning must be developed, with several studies tackling the significance of the tumor microenvironment in the genesis, development, proliferation, and overall response of cervical cancer during neoplastic processes. This review aims to analyze and contemplate the characteristics of the tumor microenvironment and its role in prognosis, progression, evasion, and invasion, including therapeutic outcome and overall survival.
- PublicationOpen AccessWnt signaling in tumors: The way to evade drugs and immunity(Frontiers in Immunology, 2019-12-20) Martín-Orozco Santiago, Elena; Sánchez-Fernández, Ana; Ortíz-Parra, Irene; Ayala-San Nicolás, María; Bioquímica y Biología Molecular B e InmunologíaWNT/b-catenin signaling is involved in many physiological processes. Its implication in embryonic development, cell migration, and polarization has been shown. Nevertheless, alterations in this signaling have also been related with pathological events such as sustaining and proliferating the cancer stem cell (CSC) subset present in the tumor bulk. Related with this, WNT signaling has been associated with the maintenance, expansion, and epithelial-mesenchymal transition of stem cells, and furthermore with two distinctive features of this tumor population: therapeutic resistance (MDR, multidrug resistance) and immune escape. These mechanisms are developed and maintained by WNT activation through the transcriptional control of the genes involved in such processes. This review focuses on the description of the best known WNT pathways and the molecules involved in them. Special attention is given to the WNT cascade proteins deregulated in tumors, which have a decisive role in tumor survival. Some of these proteins function as extrusion pumps that, in the course of chemotherapy, expel the drugs from the cells; others help the tumoral cells hide from the immune effector mechanisms. Among the WNT targets involved in drug resistance, the drug extrusion pump MDR-1 (P-GP, ABCB1) and the cell adhesion molecules from the CD44 family are highlighted. The chemokine CCL4 and the immune checkpoint proteins CD47 and PD-L1 are included in the list of WNT target molecules with a role in immunity escape. This pathway should be amain target in cancer therapy as WNT signaling activation is essential for tumor progression and survival, even in the presence of the anti-tumoral immune response and/or antineoplastic drugs. The appropriate design and combination of anti-tumoral strategies, based on the modulation of WNT mediators and/or protein targets, could negatively affect the growth of tumoral cells, improving the efficacy of these types of therapies.
- PublicationOpen AccessWNT Signaling in Tumors: The Way to Evade Drugs and Immunity(Frontiers, 2019-12-20) Martin-Orozco, Elena; Sánchez-Fernández, Ana; Ortíz-Parra, Irene; Ayala San Nicolás, María; Bioquímica y Biología Molecular B e InmunologíaWNT/β-catenin signaling is involved in many physiological processes. Its implication in embryonic development, cell migration, and polarization has been shown. Nevertheless, alterations in this signaling have also been related with pathological events such as sustaining and proliferating the cancer stem cell (CSC) subset present in the tumor bulk. Related with this, WNT signaling has been associated with the maintenance, expansion, and epithelial-mesenchymal transition of stem cells, and furthermore with two distinctive features of this tumor population: therapeutic resistance (MDR, multidrug resistance) and immune escape. These mechanisms are developed and maintained by WNT activation through the transcriptional control of the genes involved in such processes. This review focuses on the description of the best known WNT pathways and the molecules involved in them. Special attention is given to the WNT cascade proteins deregulated in tumors, which have a decisive role in tumor survival. Some of these proteins function as extrusion pumps that, in the course of chemotherapy, expel the drugs from the cells; others help the tumoral cells hide from the immune effector mechanisms. Among the WNT targets involved in drug resistance, the drug extrusion pump MDR-1 (P-GP, ABCB1) and the cell adhesion molecules from the CD44 family are highlighted. The chemokine CCL4 and the immune checkpoint proteins CD47 and PD-L1 are included in the list of WNT target molecules with a role in immunity escape. This pathway should be a main target in cancer therapy as WNT signaling activation is essential for tumor progression and survival, even in the presence of the anti-tumoral immune response and/or antineoplastic drugs. The appropriate design and combination of anti-tumoral strategies, based on the modulation of WNT mediators and/or protein targets, could negatively affect the growth of tumoral cells, improving the efficacy of these types of therapies.
- PublicationOpen AccessWNT Signaling in Tumors: The Way to Evade Drugs and Immunity(2019) Martín-Orozco Santiago, Elena; Sánchez-Fernández, Ana; Ortíz-Parra. Irene; Ayala-San Nicolás, María; Bioquímica y Biología Molecular B e Inmunología