Browsing by MeSH term "B7-H1 Antigen"
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Publication An unexpected role for PD-L1 in front-rear polarization and directional migration.(Rockefeller University Press, 2022-05-02) Sánchez-Álvarez, Miguel; del Pozo, Miguel AngelProgrammed cell death-ligand 1 (PD-L1)-mediated T cell inhibition through PD-1 is a key checkpoint frequently exploited by tumors to evade immunity. In this issue, Wang et al. (2022. J. Cell Biol.https://doi.org/10.1083/jcb.202108083) reveal an unexpected role for PD-L1 in promoting tumor cell front-rear polarity and directionally persistent cell migration, independently of PD-1.Publication Distribution of PD-L1, TROP2 and HER2- "lowness" in early triple-negative breast cancer: an opportunity for treatment de-escalation(Springer, 2024-05) Bueno, Maria Jose; Mouron, Silvana; Caleiras, Eduardo; Martínez, Mario; Manso, Luis; Colomer, Ramón; Quintela-Fandino, MiguelBACKGROUND: HER2, TROP2 and PD-L1 are novel targets in triple-negative breast cancer (TNBC). The combined expression status of these targets, and whether they can define prognostic subgroups, is currently undefined. METHODS: Immunohistochemistry was used to determine HER2, TROP2 and PD-L1 levels in 459 TNBC cases, that received in the adjuvant/neoadjuvant setting active surveillance, CMF, anthracycline-, anthracycline plus taxane-, or carboplatin-containing regimes. RESULTS: HER2-low patients with PD-L1 > 1 CPS (double-positive, herein "DP") had a mean PFS of 4768ᅠdays (95% CI: 4267-5268) versus 3522ᅠdays (95% CI: 3184-3861) for non-DP patients (P = 0.002). Regarding the received adjuvant treatment, DP patients (versus non-DP) receiving anthracyclines plus taxanes exhibited a mean PFS time of 4726 (95% CI: 4022-5430) versus 3302 (95% CI: 2818-3785) days (P = 0.039). Finally, 100% of DP patients that received a carboplatin-based regimen were long-term disease-free. CONCLUSIONS: Early HER2-low, PD-L1-positive TNBC patients have a very good prognosis, particularly if treated with anthracycline/taxane- or carboplatin-containing regimes.Publication Durvalumab plus tremelimumab for the treatment of advanced neuroendocrine neoplasms of gastroenteropancreatic and lung origin(Nature Publishing Group, 2023-05-23) Capdevila, J; Hernando, J; Teule, A; Lopez, C; Garcia-Carbonero, R; Benavent, M; Custodio, A; Garcia-Alvarez, A; Cubillo, A; Alonso, V; Carmona-Bayonas, A; Alonso-Gordoa, T; Crespo, G; Jimenez-Fonseca, P; Blanco, M; Viudez, A; La Casta, A; Sevilla, I; Segura, A; Llanos, M; Landolfi, S; Nuciforo, P; Manzano, J L; García-Carbonero, Rocio; Grupo Espanol de Tumores Neuroendocrinos y Endocrinos (GETNE); AstraZenecaSingle immune checkpoint blockade in advanced neuroendocrine neoplasms (NENs) shows limited efficacy; dual checkpoint blockade may improve treatment activity. Dune (NCT03095274) is a non-randomized controlled multicohort phase II clinical trial evaluating durvalumab plus tremelimumab activity and safety in advanced NENs. This study included 123 patients presenting between 2017 and 2019 with typical/atypical lung carcinoids (Cohort 1), G1/2 gastrointestinal (Cohort 2), G1/2 pancreatic (Cohort 3) and G3 gastroenteropancreatic (GEP) (Cohort 4) NENs; who progressed to standard therapies. Patients received 1500 mg durvalumab and 75 mg tremelimumab for up to 13 and 4 cycles (every 4 weeks), respectively. The primary objective was the 9-month clinical benefit rate (CBR) for cohorts 1-3 and 9-month overall survival (OS) rate for Cohort 4. Secondary endpoints included objective response rate, duration of response, progression-free survival according to irRECIST, overall survival, and safety. Correlation of PD-L1 expression with efficacy was exploratory. The 9-month CBR was 25.9%/35.5%/25% for Cohorts 1, 2, and 3 respectively. The 9-month OS rate for Cohort 4 was 36.1%, surpassing the futility threshold. Benefit in Cohort 4 was observed regardless of differentiation and Ki67 levels. PD-L1 combined scores did not correlate with treatment activity. Safety profile was consistent with that of prior studies. In conclusion, durvalumab plus tremelimumab is safe in NENs and shows modest survival benefit in G3 GEP-NENs; with one-third of these patients experiencing a prolonged OS.Publication Immunotherapy in NSCLC patients with brain metastases. Understanding brain tumor microenvironment and dissecting outcomes from immune checkpoint blockade in the clinic [Pre-print](Elsevier, 2020-09) Vilariño, N; Bruna, J; Nadal, E; Bosch-Barrera, J; Valiente, M; Vilariño, N.; Bruna, J.; Bosch-Barrera, J.; Valiente, M.; Nadal, E.; Government of Catalonia (España); Ministerio de Ciencia, Innovación y Universidades (España)Brain metastases are frequent complications in patients with non-small-cell lung cancer (NSCLC) associated with significant morbidity and poor prognosis. Our goal is to give a global overlook on clinical efficacy from immune checkpoint inhibitors in this setting and to review the role of biomarkers and molecular interactions in brain metastases from patients with NSCLC. We reviewed clinical trials reporting clinical outcomes of patients with NSCLC with brain metastases as well as publications assessing the tumor microenvironment and the complex molecular interactions of tumor cells with immune and resident cells in brain metastases from NSCLC biopsies or preclinical models. Although limited data are available on immunotherapy in patients with brain metastases, immune checkpoint inhibitors alone or in combination with chemotherapy have shown promising intracranial efficacy and safety results. The underlying mechanism of action of immune checkpoint inhibitors in the brain niche and their influence on tumor microenvironment are still not known. Lower PD-L1 expression and less T CD8+ infiltration were found in brain metastases compared with matched NSCLC primary tumors, suggesting an immunosuppressive microenvironment in the brain. Reactive astrocytes and tumor associated macrophages are paramount in NSCLC brain metastases and play a role in promoting tumor progression and immune evasion. Discordances in the immune profile between primary tumours and brain metastases underscore differences in the tumour microenvironment and immune system interactions within the lung and brain niche. The characterization of immune phenotype of brain metastases and dissecting the interplay among immune cells and resident stromal cells along with cancer cells is crucial to unravel effective immunotherapeutic approaches in patients with NSCLC and brain metastases.Publication Midkine rewires the melanoma microenvironment toward a tolerogenic and immune-resistant state.(Nature Publishing Group, 2020-12) Cerezo-Wallis, Daniela; Contreras-Alcalde, Marta; Troulé, Kevin; Catena, Xavier; Mucientes, Cynthia; Calvo, Tonantzin G; Cañón, Estela; Tejedo, Cristina; Pennacchi, Paula C; Hogan, Sabrina; Kölblinger, Peter; Tejero, Héctor; Chen, Andrew X; Ibarz, Nuria; Graña-Castro, Osvaldo; Martinez Garcia, Maria Dolores; Muñoz, Javier; Ortiz-Romero, Pablo; Rodriguez-Peralto, José L; Gómez-López, Gonzalo; Al-Shahrour, Fatima; Rabadán, Raúl; Levesque, Mitchell P; Olmeda, David; Soengas, MS; Melanoma Research Alliance; Worldwide Cancer Research; Asociación Española Contra el Cáncer; Instituto de Salud Carlos III; Ministerio de Ciencia y Competitividad (España); Fundación La Caixa; Marie Curie; Unión Europea. Comisión Europea. H2020An open question in aggressive cancers such as melanoma is how malignant cells can shift the immune system to pro-tumorigenic functions. Here we identify midkine (MDK) as a melanoma-secreted driver of an inflamed, but immune evasive, microenvironment that defines poor patient prognosis and resistance to immune checkpoint blockade. Mechanistically, MDK was found to control the transcriptome of melanoma cells, allowing for coordinated activation of nuclear factor-κB and downregulation of interferon-associated pathways. The resulting MDK-modulated secretome educated macrophages towards tolerant phenotypes that promoted CD8+ T cell dysfunction. In contrast, genetic targeting of MDK sensitized melanoma cells to anti-PD-1/anti-PD-L1 treatment. Emphasizing the translational relevance of these findings, the expression profile of MDK-depleted tumors was enriched in key indicators of a good response to immune checkpoint blockers in independent patient cohorts. Together, these data reveal that MDK acts as an internal modulator of autocrine and paracrine signals that maintain immune suppression in aggressive melanomas.Publication NASH limits anti-tumour surveillance in immunotherapy-treated HCC.(Nature Publishing Group, 2021-04) Pfister, Dominik; Núñez, Nicolás Gonzalo; Pinyol, Roser; Govaere, Olivier; Pinter, Matthias; Szydlowska, Marta; Gupta, Revant; Qiu, Mengjie; Deczkowska, Aleksandra; Weiner, Assaf; Müller, Florian; Sinha, Ankit; Friebel, Ekaterina; Engleitner, Thomas; Lenggenhager, Daniela; Moncsek, Anja; Heide, Danijela; Stirm, Kristin; Kosla, Jan; Kotsiliti, Eleni; Leone, Valentina; Dudek, Michael; Yousuf, Suhail; Inverso, Donato; Singh, Indrabahadur; Teijeiro, Ana; Castet, Florian; Montironi, Carla; Haber, Philipp K; Tiniakos, Dina; Bedossa, Pierre; Cockell, Simon; Younes, Ramy; Vacca, Michele; Marra, Fabio; Schattenberg, Jörn M; Allison, Michael; Bugianesi, Elisabetta; Ratziu, Vlad; Pressiani, Tiziana; D'Alessio, Antonio; Personeni, Nicola; Rimassa, Lorenza; Daly, Ann K; Scheiner, Bernhard; Pomej, Katharina; Kirstein, Martha M; Vogel, Arndt; Peck-Radosavljevic, Markus; Hucke, Florian; Finkelmeier, Fabian; Waidmann, Oliver; Trojan, Jörg; Schulze, Kornelius; Wege, Henning; Koch, Sandra; Weinmann, Arndt; Bueter, Marco; Rössler, Fabian; Siebenhüner, Alexander; De Dosso, Sara; Mallm, Jan-Philipp; Umansky, Viktor; Jugold, Manfred; Luedde, Tom; Schietinger, Andrea; Schirmacher, Peter; Emu, Brinda; Augustin, Hellmut G; Billeter, Adrian; Müller-Stich, Beat; Kikuchi, Hiroto; Duda, Dan G; Kütting, Fabian; Waldschmidt, Dirk-Thomas; Ebert, Matthias Philip; Rahbari, Nuh; Mei, Henrik E; Schulz, Axel Ronald; Ringelhan, Marc; Malek, Nisar; Spahn, Stephan; Bitzer, Michael; Ruiz de Galarreta, Marina; Lujambio, Amaia; Dufour, Jean-Francois; Marron, Thomas U; Kaseb, Ahmed; Kudo, Masatoshi; Huang, Yi-Hsiang; Djouder, Nabil; Wolter, Katharina; Zender, Lars; Marche, Parice N; Decaens, Thomas; Pinato, David J; Rad, Roland; Mertens, Joachim C; Weber, Achim; Unger, Kristian; Meissner, Felix; Roth, Susanne; Jilkova, Zuzana Macek; Claassen, Manfred; Anstee, Quentin M; Amit, Ido; Knolle, Percy; Becher, Burkhard; Llovet, Josep M; Heikenwalder, Mathias; Deutsche Forschungsgemeinschaft (Alemania); European Molecular Biology Organization; Unión Europea. Comisión Europea. H2020; Howard Hughes Medical Institute; Israel Science Foundation; Cancer Research UK (Reino Unido); Asociación Española Contra el Cáncer; United States Department of Health and Human Services; Government of Catalonia (España); Instituto de Salud Carlos IIIHepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.Publication PD-L1ATTAC mice reveal the potential of depleting PD-L1 expressing cells in cancer therapy.(Impact Journals, 2023-03-22) Fueyo-Marcos, Elena; Lopez-Pernas, Gema; Fustero-Torre, Coral; Antón, Marta Elena; Al-Shahrour, Fátima; Fernández-Capetillo, Oscar; Murga, Matilde; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Asociación Española Contra el Cáncer; Instituto de Salud Carlos III; Ministerio de Ciencia, Innovación y Universidades (España)Antibodies targeting the PD-1 receptor and its ligand PD-L1 have shown impressive responses in some tumors of bad prognosis. We hypothesized that, since immunosuppressive cells might present several immune checkpoints on their surface, the selective elimination of PD-L1 expressing cells could be efficacious in enabling the activation of antitumoral immune responses. To address this question, we developed an inducible suicidal knock-in mouse allele of Pd-l1 (PD-L1ATTAC) which allows for the tracking and specific elimination of PD-L1-expressing cells in adult tissues. Consistent with our hypothesis, elimination of PD-L1 expressing cells from the mouse peritoneum increased the septic response to lipopolysaccharide (LPS), due to an exacerbated inflammatory response to the endotoxin. In addition, mice depleted of PD-L1+ cells were resistant to colon cancer peritoneal allografts, which was associated with a loss of immunosuppressive B cells and macrophages, concomitant with an increase in activated cytotoxic CD8 T cells. Collectively, these results illustrate the usefulness of PD-L1ATTAC mice for research in immunotherapy and provide genetic support to the concept of targeting PD-L1 expressing cells in cancer.Publication Targeting Protein Kinases to Enhance the Response to anti-PD-1/PD-L1 Immunotherapy.(2019-05-09) García-Aranda, Marilina; Redondo, MaximinoThe interaction between programmed cell death protein (PD-1) and its ligand (PD-L1) is one of the main pathways used by some tumors to escape the immune response. In recent years, immunotherapies based on the use of antibodies against PD-1/PD-L1 have been postulated as a great promise for cancer treatment, increasing total survival compared to standard therapy in different tumors. Despite the hopefulness of these results, a significant percentage of patients do not respond to such therapy or will end up evolving toward a progressive disease. Besides their role in PD-L1 expression, altered protein kinases in tumor cells can limit the effectiveness of PD-1/PD-L1 blocking therapies at different levels. In this review, we describe the role of kinases that appear most frequently altered in tumor cells and that can be an impediment for the success of immunotherapies as well as the potential utility of protein kinase inhibitors to enhance the response to such treatments.Publication Tumor microenvironment gene expression profiles associated to complete pathological response and disease progression in resectable NSCLC patients treated with neoadjuvant chemoimmunotherapy.(2022) Casarrubios, Marta; Provencio, Mariano; Nadal, Ernest; Insa, Amelia; Del Rosario García-Campelo, María; Lázaro-Quintela, Martín; Dómine, Manuel; Majem, Margarita; Rodriguez-Abreu, Delvys; Martinez-Marti, Alex; De Castro Carpeño, Javier; Cobo, Manuel; López Vivanco, Guillermo; Del Barco, Edel; Bernabé, Reyes; Viñolas, Nuria; Barneto Aranda, Isidoro; Massuti, Bartomeu; Sierra-Rodero, Belén; Martinez-Toledo, Cristina; Fernández-Miranda, Ismael; Serna-Blanco, Roberto; Romero, Atocha; Calvo, Virginia; Cruz-Bermúdez, AlbertoNeoadjuvant chemoimmunotherapy for non-small cell lung cancer (NSCLC) has improved pathological responses and survival rates compared with chemotherapy alone, leading to Food and Drug Administration (FDA) approval of nivolumab plus chemotherapy for resectable stage IB-IIIA NSCLC (AJCC 7th edition) without ALK or EGFR alterations. Unfortunately, a considerable percentage of tumors do not completely respond to therapy, which has been associated with early disease progression. So far, it is impossible to predict these events due to lack of knowledge. In this study, we characterized the gene expression profile of tumor samples to identify new biomarkers and mechanisms behind tumor responses to neoadjuvant chemoimmunotherapy and disease recurrence after surgery. Tumor bulk RNA sequencing was performed in 16 pretreatment and 36 post-treatment tissue samples from 41 patients with resectable stage IIIA NSCLC treated with neoadjuvant chemoimmunotherapy from NADIM trial. A panel targeting 395 genes related to immunological processes was used. Tumors were classified as complete pathological response (CPR) and non-CPR, based on the total absence of viable tumor cells in tumor bed and lymph nodes tested at surgery. Differential-expressed genes between groups and pathway enrichment analysis were assessed using DESeq2 and gene set enrichment analysis. CIBERSORTx was used to estimate the proportions of immune cell subtypes. CPR tumors had a stronger pre-established immune infiltrate at baseline than non-CPR, characterized by higher levels of IFNG, GZMB, NKG7, and M1 macrophages, all with a significant area under the receiver operating characteristic curve (ROC) >0.9 for CPR prediction. A greater effect of neoadjuvant therapy was also seen in CPR tumors with a reduction of tumor markers and IFNγ signaling after treatment. Additionally, the higher expression of several genes, including AKT1, BST2, OAS3, or CD8B; or higher dendritic cells and neutrophils proportions in post-treatment non-CPR samples, were associated with relapse after surgery. Also, high pretreatment PD-L1 and tumor mutational burden levels influenced the post-treatment immune landscape with the downregulation of proliferation markers and type I interferon signaling molecules in surgery samples. Our results reinforce the differences between CPR and non-CPR responses, describing possible response and relapse immune mechanisms, opening the possibility of therapy personalization of immunotherapy-based regimens in the neoadjuvant setting of NSCLC.