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3. Apoptosis, a Metabolic "Head-to-Head" between Tumor and T Cells: Implications for Immunotherapy.

Author

Franzese, Ornella, Ancona, Pietro, Bianchi, Nicoletta, and Aguiari, Gianluca

Subjects
*T cells, *APOPTOSIS, *CELL death, *CANCER cells, *IMMUNOTHERAPY, *TUMOR microenvironment
Abstract

Induction of apoptosis represents a promising therapeutic approach to drive tumor cells to death. However, this poses challenges due to the intricate nature of cancer biology and the mechanisms employed by cancer cells to survive and escape immune surveillance. Furthermore, molecules released from apoptotic cells and phagocytes in the tumor microenvironment (TME) can facilitate cancer progression and immune evasion. Apoptosis is also a pivotal mechanism in modulating the strength and duration of anti-tumor T-cell responses. Combined strategies including molecular targeting of apoptosis, promoting immunogenic cell death, modulating immunosuppressive cells, and affecting energy pathways can potentially overcome resistance and enhance therapeutic outcomes. Thus, an effective approach for targeting apoptosis within the TME should delicately balance the selective induction of apoptosis in tumor cells, while safeguarding survival, metabolic changes, and functionality of T cells targeting crucial molecular pathways involved in T-cell apoptosis regulation. Enhancing the persistence and effectiveness of T cells may bolster a more resilient and enduring anti-tumor immune response, ultimately advancing therapeutic outcomes in cancer treatment. This review delves into the pivotal topics of this multifaceted issue and suggests drugs and druggable targets for possible combined therapies. [ABSTRACT FROM AUTHOR]

Published
2024
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6. CD28/PD1 co-expression: dual impact on CD8+ T cells in peripheral blood and tumor tissue, and its significance in NSCLC patients' survival and ICB response.

Author

Palermo, Belinda, Franzese, Ornella, Frisullo, Giuseppe, D'Ambrosio, Lorenzo, Panetta, Mariangela, Campo, Giulia, D'Andrea, Daniel, Sperduti, Isabella, De Nicola, Francesca, Goeman, Frauke, Gallina, Filippo, Visca, Paolo, Facciolo, Francesco, and Nisticò, Paola

Subjects
*T cells, *BLOOD cells, *NON-small-cell lung carcinoma, *IMMUNE checkpoint proteins, *T-cell exhaustion
Abstract

Background: Immune checkpoint blockade (ICB) has significantly prolonged survival of non-small cell lung cancer (NSCLC) patients, although most patients develop mechanisms of resistance. Recently single-cell RNA-sequencing (scRNA-Seq) revealed a huge T-cell phenotypic and (dys)functional state variability. Accordingly, T-cell exhaustion is recognized as a functional adaptation, with a dynamic progression from a long-lived "pre-exhausted stem-like progenitor" to a "terminally exhausted" state. In this scenario it is crucial to understand the complex interplay between co-stimulatory and inhibitory molecules in CD8+ T-cell functionality. Methods: To gain a baseline landscape of the composition, functional states, and transcriptomic signatures predictive of prognosis, we analyzed CD8+ T-cell subsets characterized by the presence/absence of PD1 and CD28 from periphery, adjacent non-tumor tissue and tumor site of a cohort of treatment-naïve NSCLC patients, by integrated multiparametric flow cytometry, targeted multi-omic scRNA-seq analyses, and computational pipelines. Results: Despite the increased PD1 levels, an improved PD1+CD28+ T-cell polyfunctionality was observed with the transition from periphery to tumor site, associated with lack of TIGIT, TIM-3 and LAG-3, but not with Ag-experienced-marker CD11a. Differently from CD28+ T cells, the increased PD1 levels in the tumor were associated with reduced functionality in PD1+CD28− T cells. CD11ahigh, although expressed only in a small fraction of this subset, still sustained its functionality. Absence of TIGIT, TIM-3 and CTLA-4, alone or combined, was beneficial to CD28− T cells. Notably, we observed distinct TRM phenotypes in the different districts, with CD28+ T cells more capable of producing TGFβ in the periphery, potentially contributing to elevated CD103 levels. In contrast CD28− TRM mainly produced CXCL13 within the tumor. ScRNA-seq revealed 5 different clusters for each of the two subsets, with distinctive transcriptional profiles in the three districts. By interrogating the TCGA dataset of patients with lung adenocarcinoma (LUAD) and metastatic NSCLC treated with atezolizumab, we found signatures of heterogeneous TRM and "pre-exhausted" long-lived effector memory CD8+ T cells associated with improved response to ICB only in the presence of CD28. Conclusions: Our findings identify signatures able to stratify survival of LUAD patients and predict ICB response in advanced NSCLC. CD28 is advocated as a key determinant in the signatures identified, in both periphery and tumor site, thus likely providing feasible biomarkers of ICB response. [ABSTRACT FROM AUTHOR]

Published
2023
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8. P38 signaling inhibits mTORC1-independent autophagy in senescent human [CD8.sup.+] t cells

Author

Henson, Sian M., Lanna, Alessio, Riddell, Natalie E., Franzese, Ornella, Macaulay, Richard, Griffiths, Stephen J., Puleston, Daniel J., Watson, Alexander Scarth, Simon, Anna Katharina, Tooze, Sharon A., and Akbar, Arne N.

Subjects
Cells -- Aging, T cells -- Physiological aspects, Cell research, Autophagy (Cytology) -- Research, Cell metabolism -- Research, Cellular signal transduction -- Research, Health care industry
Abstract

T cell senescence is thought to contribute to immune function decline, but the pathways that mediate senescence in these cells are not clear. Here, we evaluated T cell populations from healthy volunteers and determined that human [CD8.sup.+] effector memory T cells that reexpress the naive T cell marker CD45RA have many characteristics of cellular senescence, including decreased proliferation, defective mitochondrial function, and elevated levels of both ROS and p38 MAPK. Despite their apparent senescent state, we determined that these cells secreted high levels of both TNF-α and IFN-γ and showed potent cytotoxic activity. We found that the senescent CD45RA-expressing population engaged anaerobic glycolysis to generate energy for effector functions. Furthermore, inhibition of p38 MAPK signaling in senescent [CD8.sup.+] T cells increased their proliferation, telomerase activity, mitochondrial biogenesis, and fitness; however, the extra energy required for these processes did not arise from increased glucose uptake or oxidative phosphorylation. Instead, p38 MAPK blockade in these senescent cells induced an increase in autophagy through enhanced interactions between p38 interacting protein (p38IP) and autophagy protein 9 (ATG9) in an mTOR-independent manner. Together, our findings describe fundamental metabolic requirements of senescent primary human [CD8.sup.+] T cells and demonstrate that p38 MAPK blockade reverses senescence via an mTOR- independent pathway., Introduction Cellular senescence has predominantly been characterized using fibroblast models, where it is defined as the irreversible loss of proliferative capacity despite continued viability and metabolic activity (1). This arrested [...]

Published
2014
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12. hTERT Transduction Extends the Lifespan of Primary Pediatric Low-Grade Glioma Cells While Preserving the Biological Response to NGF

Author

Franzese, Ornella, Di Francesco, Angela M, Meco, Daniela, Graziani, Grazia, Cusano, Gabriella, Levati, Lauretta, Riccardi, Riccardo, Ruggiero, Antonio, Ruggiero, Antonio (ORCID:0000-0002-6052-3511), Franzese, Ornella, Di Francesco, Angela M, Meco, Daniela, Graziani, Grazia, Cusano, Gabriella, Levati, Lauretta, Riccardi, Riccardo, Ruggiero, Antonio, and Ruggiero, Antonio (ORCID:0000-0002-6052-3511)

Abstract

The neurotrophin nerve growth factor (NGF) modulates the growth of human gliomas and is able to induce cell differentiation through the engagement of tropomyosin receptor kinase A (TrkA) receptor, although the role played in controlling glioma survival has proved controversial. Unfortunately, the slow growth rate of low-grade gliomas (LGG) has made it difficult to investigate NGF effects on these tumors in preclinical models. In fact, patient-derived low-grade human astrocytoma cells duplicate only a limited number of times in culture before undergoing senescence. Nevertheless, replicative senescence can be counteracted by overexpression of hTERT, the catalytic subunit of telomerase, which potentially increases the proliferative potential of human cells without inducing cancer-associated changes. We have extended, by hTERT transduction, the proliferative in vitro potential of a human LGG cell line derived from a pediatric pilocytic astrocytoma (PA) surgical sample. Remarkably, the hTERT-transduced LGG cells showed a behavior similar to that of the parental line in terms of biological responses to NGF treatment, including molecular events associated with induction of NGF-related differentiation. Therefore, transduction of LGG cells with hTERT can provide a valid approach to increase the in vitro life-span of patient-derived astrocytoma primary cultures, characterized by a finite proliferative potential.

Published
2021

19. Drug-induced xenogenization of tumors: A possible role in the immune control of malignant cell growth in the brain?

Author

Franzese, Ornella, Battaini, Fiorenzo, Graziani, Grazia, Tentori, Lucio, Barbaccia, Maria Luisa, Aquino, Angelo, Roselli, Mario, Fuggetta, Maria Pia, Bonmassar, Enzo, and Torino, Francesco

Subjects
0301 basic medicine, Temozolomide (PubChem CID: 5394), Adoptive cell transfer, DNA repair, medicine.medical_treatment, Cell, Cancer immunotherapy, Drug-induced neoantigens, 03 medical and health sciences, Immune checkpoint inhibitors, 0302 clinical medicine, Immune system, Cyclophosphamide (PubChem CID: 2907), DNA repair enzyme, DTIC (Dacarbazine) (PubChem CID: 5353562), GPI 15427 (PubChem CID: 11739525), Lomeguatrib (PubChem CID: 3025944), MGMT inhibitors, NU 1025 (PubChem CID: 63306), Temozolomide, Neoplasms, medicine, Cytotoxic T cell, Animals, Humans, Pharmacology, Leukemia, business.industry, Brain Neoplasms, Immunogenicity, Immunity, Settore BIO/14, Brain, DNA Methylation, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Mutation, Cancer research, Immunotherapy, Triazenes, business, T-Lymphocytes, Cytotoxic
Abstract

In recent years, immune checkpoint inhibitors (ICpI) have provided the ground to bring tumor immunity back to life thanks to their capacity to afford a real clinical benefit in terms of patient's survival. Essential to ICpI success is the presence of tumor-associated neoantigens generated by non-synonymous mutations, since a direct relationship between mutation load of malignant cells and susceptibility to ICpI has been confidently established. However, it has been also suggested that high intratumor heterogeneity (ITH) associated with subclonal neoantigens could not elicit adequate immune responses. Several years ago we discovered that in vivo treatment of leukemic mice with triazene compounds (TZC) produces a marked increase of leukemia cell immunogenicity [a phenomenon termed Drug-Induced Xenogenization (DIX)] through point mutations able to generate strong tumor neoantigens (Drug-Induced Neoantigens, DIN). Immunogenic mutations are produced by TZC-dependent methylation of O6-guanine of DNA, that is suppressed by the DNA repair protein methyl-guaninemethyltransferase (MGMT). This minireview illustrates preclinical investigations conducted in animal models where DIN-positive murine leukemia cells were inoculated intracerebrally into histocompatible mice. The analysis of the literature indicates that the growth of xenogenized malignant cells is controlled by anti-DIN graft responses and by intra-cerebral or intravenous adoptive transfer of anti-DIN cytotoxic T lymphocytes. This survey reminds also that PARP inhibitors increase substantially the antitumor activity of TZC and can be administered with the intent of suppressing more efficiently tumor load and possibly reducing ITH through downsizing the polyclonality of xenogenized tumor cell population. Finally, the present report illustrates a hypothetical clinical protocol that could be considered as an example of future development of DIXbased tumor immuno-chemotherapy in brain malignancies. The protocol involves oral or intravenous administration of TZC along with loco-regional (i.e. intracerebral "wafer") treatment with agents able to increase tumor cell sensitivity to the cytotoxic and xenogenizing effects of TZC (i.e. MGMT and PARP inhibitors) without enhancing the systemic toxicity of these DNA methylating compounds.

Published
2018

20. Fatty acid synthase inhibitor orlistat impairs cell growth and down-regulates PD-L1 expression of a human T-cell leukemia line

Author

Cioccoloni, Giorgia, primary, Aquino, Angelo, additional, Notarnicola, Maria, additional, Caruso, Maria Gabriella, additional, Bonmassar, Enzo, additional, Zonfrillo, Manuela, additional, Caporali, Simona, additional, Faraoni, Isabella, additional, Villivà, Cristina, additional, Fuggetta, Maria Pia, additional, and Franzese, Ornella, additional

Published
2019
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24. Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients

Author

Palermo, Belinda, primary, Franzese, Ornella, additional, Donna, Cosmo Di, additional, Panetta, Mariangela, additional, Quintarelli, Concetta, additional, Sperduti, Isabella, additional, Gualtieri, Novella, additional, Foddai, Maria Laura, additional, Proietti, Enrico, additional, Ferraresi, Virginia, additional, Ciliberto, Gennaro, additional, and Nisticò, Paola, additional

Published
2018
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28. Melanoma and immunotherapy bridge 2015

Author

Nanda, Vashisht G. Y., Peng, Weiyi, Hwu, Patrick, Davies, Michael A., Ciliberto, Gennaro, Fattore, Luigi, Malpicci, Debora, Aurisicchio, Luigi, Ascierto, Paolo Antonio, Croce, Carlo M., Mancini, Rita, Spranger, Stefani, Gajewski, Thomas F., Wang, Yangyang, Ferrone, Soldano, Vanpouille-Box, Claire, Wennerberg, Erik, Pilones, Karsten A., Formenti, Silvia C., Demaria, Sandra, Tang, Haidong, Wang, Yang, Fu, Yang-Xin, Dummer, Reinhard, Puzanov, Igor, Tarhini, Ahmad, Chauvin, Joe-Marc, Pagliano, Ornella, Fourcade, Julien, Sun, Zhaojun, Wang, Hong, Sanders, Cindy, Kirkwood, John M., Chen, Tseng-hui Timothy, Maurer, Mark, Korman, Alan J., Zarour, Hassane M., Stroncek, David F., Huber, Veronica, Rivoltini, Licia, Thurin, Magdalena, Rau, Tilman, Lugli, Alessandro, Pagès, Franck, Camarero, Jorge, Sancho, Arantxa, Jommi, Claudio, de Coaña, Yago Pico, Wolodarski, Maria, Yoshimoto, Yuya, Gentilcore, Giusy, Poschke, Isabel, Masucci, Giuseppe V., Hansson, Johan, Kiessling, Rolf, Scognamiglio, Giosuè, Sabbatino, Francesco, Marino, Federica Zito, Anniciello, Anna Maria, Cantile, Monica, Cerrone, Margherita, Scala, Stefania, D’alterio, Crescenzo, Ianaro, Angela, Cirin, Giuseppe, Liguori, Giuseppina, Bott, Gerardo, Chapman, Paul B., Robert, Caroline, Larkin, James, Haanen, John B., Ribas, Antoni, Hogg, David, Hamid, Omid, Testori, Alessandro, Lorigan, Paul, Sosman, Jeffrey A., Flaherty, Keith T., Yue, Huibin, Coleman, Shelley, Caro, Ivor, Hauschild, Axel, McArthur, Grant A., Sznol, Mario, Callahan, Margaret K., Kluger, Harriet, Postow, Michael A., Gordan, RuthAnn, Segal, Neil H., Rizvi, Naiyer A., Lesokhin, Alexander, Atkins, Michael B., Burke, Matthew M., Ralabate, Amanda, Rivera, Angel, Kronenberg, Stephanie A., Agunwamba, Blessing, Ruisi, Mary, Horak, Christine, Jiang, Joel, Wolchok, Jedd, Ascierto, Paolo A., Liszkay, Gabriella, Maio, Michele, Mandalà, Mario, Demidov, Lev, Stoyakovskiy, Daniil, Thomas, Luc, de la Cruz-Merino, Luis, Atkinson, Victoria, Dutriaux, Caroline, Garbe, Claus, Wongchenko, Matthew, Chang, Ilsung, Koralek, Daniel O., Rooney, Isabelle, Yan, Yibing, Dréno, Brigitte, Sullivan, Ryan, Patel, Manish, Hodi, Stephen, Amaria, Rodabe, Boasberg, Peter, Wallin, Jeffrey, He, Xian, Cha, Edward, Richie, Nicole, Ballinger, Marcus, Smith, David C., Bauer, Todd M., Wasser, Jeffrey S., Luke, Jason J., Balmanoukian, Ani S., Kaufman, David R., Zhao, Yufan, Maleski, Janet, Leopold, Lance, Gangadhar, Tara C., Long, Georgina V., Michielin, Olivier, VanderWalde, Ari, Andtbacka, Robert H. I., Cebon, Jonathan, Fernandez, Eugenio, Malvehy, Josep, Olszanski, Anthony J., Gause, Christine, Chen, Lisa, Chou, Jeffrey, Stephen Hodi, F., Brady, Benjamin, Mortier, Laurent, Hassel, Jessica C., Rutkowski, Piotr, McNeil, Catriona, Kalinka-Warzocha, Ewa, Lebbé, Celeste, Ny, Lars, Chacon, Matias, Queirolo, Paola, Loquai, Carmen, Cheema, Parneet, Berrocal, Alfonso, Eizmendi, Karmele Mujika, Bar-Sela, Gil, Hardy, Helene, Weber, Jeffrey S., Grob, Jean-Jacques, Marquez-Rodas, Ivan, Schmidt, Henrik, Briscoe, Karen, Baurain, Jean-François, Wolchok, Jedd D., Pinto, Rosamaria, De Summa, Simona, Garrisi, Vito Michele, Strippoli, Sabino, Azzariti, Amalia, Guida, Gabriella, Guida, Michele, Tommasi, Stefania, Jacquelot, Nicolas, Enot, David, Flament, Caroline, Pitt, Jonathan M., Vimond, Nadège, Blattner, Carolin, Yamazaki, Takahiro, Roberti, Maria-Paula, Vetizou, Marie, Daillere, Romain, Poirier-Colame, Vichnou, la Semeraro, Michaë, Caignard, Anne, Slingluff, Craig L, Sallusto, Federica, Rusakiewicz, Sylvie, Weide, Benjamin, Marabelle, Aurélien, Kohrt, Holbrook, Dalle, Stéphane, Cavalcanti, Andréa, Kroemer, Guido, Di Giacomo, Anna Maria, Maio, Michaele, Wong, Phillip, Yuan, Jianda, Umansky, Viktor, Eggermont, Alexander, Zitvogel, Laurence, Anna, Passarelli, Marco, Tucci, Stefania, Stucci, Francesco, Mannavola, Mariaelena, Capone, Gabriele, Madonna, Antonio, Ascierto Paolo, Franco, Silvestris, Roberti, María Paula, Enot, David P., Semeraro, Michaela, Jégou, Sarah, Flores, Camila, Kwon, Byoung S., Anderson, Ana Carrizossa, Borg, Christophe, Aubin, François, Ayyoub, Maha, De Presbiteris, Anna Lisa, Cordaro, Fabiola Gilda, Camerlingo, Rosa, Fratangelo, Federica, Mozzillo, Nicola, Pirozzi, Giuseppe, Patriarca, Eduardo J., Caputo, Emilia, Motti, Maria Letizia, Falcon, Rosaria, Miceli, Roberta, Capone, Mariaelena, Madonna, Gabriele, Mallardo, Domenico, Carrier, Maria Vincenza, Panza, Elisabetta, De Cicco, Paola, Armogida, Chiara, Ercolano, Giuseppe, Botti, Gerardo, Cirino, Giuseppe, Sandru, Angela, Blank, Miri, Balatoni, Timea, Olasz, Judit, Farkas, Emil, Szollar, Andras, Savolt, Akos, Godeny, Maria, Csuka, Orsolya, Horvath, Szabolcs, Eles, Klara, Shoenfeld, Yehuda, Kasler, Miklos, Costantini, Susan, Capone, Francesca, Moradi, Farnaz, Berglund, Pontus, Leandersson, Karin, Linnskog, Rickard, Andersson, Tommy, Prasad, Chandra Prakash, Nigro, Cristiana Lo, Lattanzio, Laura, Wang, Hexiao, Proby, Charlotte, Syed, Nelofer, Occelli, Marcella, Cauchi, Carolina, Merlano, Marco, Harwood, Catherine, Thompson, Alastair, Crook, Tim, Bifulco, Katia, Ingangi, Vincenzo, Minopoli, Michele, Ragone, Concetta, Pessi, Antonello, Mannavola, Francesco, D’Oronzo, Stella, Felici, Claudia, Tucci, Marco, Doronzo, Antonio, Silvestris, Franco, Ferretta, Anna, Guida, Stefania, Maida, Imma, Cocco, Tiziana, Passarelli, Anna, Quaresmini, Davide, Franzese, Ornella, Palermo, Belinda, Di Donna, Cosmo, Sperduti, Isabella, Foddai, MariaLaura, Stabile, Helena, Gismondi, Angela, Santoni, Angela, Nisticò, Paola, Sponghini, Andrea P., Platini, Francesca, Marra, Elena, Rondonotti, David, Alabiso, Oscar, Fierro, Maria T., Savoia, Paola, Stratica, Florian, Quaglino, Pietro, Di Monta, Gianluca, Corrado, Caracò, Di Marzo, Massimiliano, Ugo, Marone, Di Cecilia, Maria Luisa, Nicola, Mozzillo, Fusciello, Celeste, Marra, Antonio, Guarrasi, Rosario, Baldi, Carlo, Russo, Rosa, Di Giulio, Giovanni, Faiola, Vincenzo, Zeppa, Pio, Pepe, Stefano, Gambale, Elisabetta, Carella, Consiglia, Di Paolo, Alessandra, De Tursi, Michele, Marra, Laura, De Murtas, Fara, Sorrentino, Valeria, Voinea, Silviu, Panaitescu, Eugenia, Bolovan, Madalina, Stanciu, Adina, Cinca, Sabin, Botti, Chiara, Aquino, Gabriella, Anniciello, Annamaria, Fortes, Cristina, Mastroeni, Simona, Caggiati, Alessio, Passarelli, Francesca, Zappalà, Alba, Capuano, Maria, Bono, Riccardo, Nudo, Maurizio, Marino, Claudia, Michelozzi, Paola, De Biasio, Valeria, Battarra, Vincenzo C., Formenti, Silvia, Ascierto, Maria Libera, McMiller, Tracee L., Berger, Alan E., Danilova, Ludmila, Anders, Robert A., Netto, George J., Xu, Haiying, Pritchard, Theresa S., Fan, Jinshui, Cheadle, Chris, Cope, Leslie, Drake, Charles G., Pardoll, Drew M., Taube, Janis M., Topalian, Suzanne L., Gnjatic, Sacha, Nataraj, Sarah, Imai, Naoko, Rahman, Adeeb, Jungbluth, Achim A., Pan, Linda, Venhaus, Ralph, Park, Andrew, Lehmann, Frédéric F., Lendvai, Nikoletta, Cohen, Adam D., Cho, Hearn J., Daniel, Speiser, and Hirsh, Vera

Subjects
Medicine(all), Biochemistry, Genetics and Molecular Biology(all), Meeting Abstracts
Abstract

Table of contents MELANOMA BRIDGE 2015 KEYNOTE SPEAKER PRESENTATIONS Molecular and immuno-advances K1 Immunologic and metabolic consequences of PI3K/AKT/mTOR activation in melanoma Vashisht G. Y. Nanda, Weiyi Peng, Patrick Hwu, Michael A. Davies K2 Non-mutational adaptive changes in melanoma cells exposed to BRAF and MEK inhibitors help the establishment of drug resistance Gennaro Ciliberto, Luigi Fattore, Debora Malpicci, Luigi Aurisicchio, Paolo Antonio Ascierto, Carlo M. Croce, Rita Mancini K3 Tumor-intrinsic beta-catenin signaling mediates tumor-immune avoidance Stefani Spranger, Thomas F. Gajewski K4 Intracellular tumor antigens as a source of targets of antibody-based immunotherapy of melanoma Yangyang Wang, Soldano Ferrone Combination therapies K5 Harnessing radiotherapy to improve responses to immunotherapy in cancer Claire Vanpouille-Box, Erik Wennerberg, Karsten A. Pilones, Silvia C. Formenti, Sandra Demaria K6 Creating a T cell-inflamed tumor microenvironment overcomes resistance to checkpoint blockade Haidong Tang, Yang Wang, Yang-Xin Fu K7 Biomarkers for treatment decisions? Reinhard Dummer K8 Combining oncolytic therapies in the era of checkpoint inhibitors Igor Puzanov K9 Immune checkpoint blockade for melanoma: should we combine or sequence ipilimumab and PD-1 antibody therapy? Michael A. Postow News in immunotherapy K10 An update on adjuvant and neoadjuvant therapy for melanom Ahmad Tarhini K11 Targeting multiple inhibitory receptors in melanoma Joe-Marc Chauvin, Ornella Pagliano, Julien Fourcade, Zhaojun Sun, Hong Wang, Cindy Sanders, John M. Kirkwood, Tseng-hui Timothy Chen, Mark Maurer, Alan J. Korman, Hassane M. Zarour K12 Improving adoptive immune therapy using genetically engineered T cells David F. Stroncek Tumor microenvironment and biomarkers K13 Myeloid cells and tumor exosomes: a crosstalk for assessing immunosuppression? Veronica Huber, Licia Rivoltini K14 Update on the SITC biomarker taskforce: progress and challenges Magdalena Thurin World-wide immunoscore task force: an update K15 The immunoscore in colorectal cancer highlights the importance of digital scoring systems in surgical pathology Tilman Rau, Alessandro Lugli K16 The immunoscore: toward an integrated immunomonitoring from the diagnosis to the follow up of cancer’s patients Franck Pagès Economic sustainability of melanoma treatments: regulatory, health technology assessment and market access issues K17 Nivolumab, the regulatory experience in immunotherapy Jorge Camarero, Arantxa Sancho K18 Evidence to optimize access for immunotherapies Claudio Jommi ORAL PRESENTATIONS Molecular and immuno-advances O1 Ipilimumab treatment results in CD4 T cell activation that is concomitant with a reduction in Tregs and MDSCs Yago Pico de Coaña, Maria Wolodarski, Yuya Yoshimoto, Giusy Gentilcore, Isabel Poschke, Giuseppe V. Masucci, Johan Hansson, Rolf Kiessling O2 Evaluation of prognostic and therapeutic potential of COX-2 and PD-L1 in primary and metastatic melanoma Giosuè Scognamiglio, Francesco Sabbatino, Federica Zito Marino, Anna Maria Anniciello, Monica Cantile, Margherita Cerrone, Stefania Scala, Crescenzo D’alterio, Angela Ianaro, Giuseppe Cirino, Paolo Antonio Ascierto, Giuseppina Liguori, Gerardo Botti O3 Vemurafenib in patients with BRAFV600 mutation–positive metastatic melanoma: final overall survival results of the BRIM-3 study Paul B. Chapman, Caroline Robert, James Larkin, John B. Haanen, Antoni Ribas, David Hogg, Omid Hamid, Paolo Antonio Ascierto, Alessandro Testori, Paul Lorigan, Reinhard Dummer, Jeffrey A. Sosman, Keith T. Flaherty, Huibin Yue, Shelley Coleman, Ivor Caro, Axel Hauschild, Grant A. McArthur O4 Updated survival, response and safety data in a phase 1 dose-finding study (CA209-004) of concurrent nivolumab (NIVO) and ipilimumab (IPI) in advanced melanoma Mario Sznol, Margaret K. Callahan, Harriet Kluger, Michael A. Postow, RuthAnn Gordan, Neil H. Segal, Naiyer A. Rizvi, Alexander Lesokhin, Michael B. Atkins, John M. Kirkwood, Matthew M. Burke, Amanda Ralabate, Angel Rivera, Stephanie A. Kronenberg, Blessing Agunwamba, Mary Ruisi, Christine Horak, Joel Jiang, Jedd Wolchok Combination therapies O5 Efficacy and correlative biomarker analysis of the coBRIM study comparing cobimetinib (COBI) + vemurafenib (VEM) vs placebo (PBO) + VEM in advanced BRAF-mutated melanoma patients (pts) Paolo A. Ascierto, Grant A. McArthur, James Larkin, Gabriella Liszkay, Michele Maio, Mario Mandalà, Lev Demidov, Daniil Stoyakovskiy, Luc Thomas, Luis de la Cruz-Merino, Victoria Atkinson, Caroline Dutriaux, Claus Garbe, Matthew Wongchenko, Ilsung Chang, Daniel O. Koralek, Isabelle Rooney, Yibing Yan, Antoni Ribas, Brigitte Dréno O6 Preliminary clinical safety, tolerability and activity results from a Phase Ib study of atezolizumab (anti-PDL1) combined with vemurafenib in BRAFV600-mutant metastatic melanoma Ryan Sullivan, Omid Hamid, Manish Patel, Stephen Hodi, Rodabe Amaria, Peter Boasberg, Jeffrey Wallin, Xian He, Edward Cha, Nicole Richie, Marcus Ballinger, Patrick Hwu O7 Preliminary safety and efficacy data from a phase 1/2 study of epacadostat (INCB024360) in combination with pembrolizumab in patients with advanced/metastatic melanoma Thomas F. Gajewski, Omid Hamid, David C. Smith, Todd M. Bauer, Jeffrey S. Wasser, Jason J. Luke, Ani S. Balmanoukian, David R. Kaufman, Yufan Zhao, Janet Maleski, Lance Leopold, Tara C. Gangadhar O8 Primary analysis of MASTERKEY-265 phase 1b study of talimogene laherparepvec (T-VEC) and pembrolizumab (pembro) for unresectable stage IIIB-IV melanoma Reinhard Dummer, Georgina V. Long, Antoni Ribas, Igor Puzanov, Olivier Michielin, Ari VanderWalde, Robert H.I. Andtbacka, Jonathan Cebon, Eugenio Fernandez, Josep Malvehy, Anthony J. Olszanski, Thomas F. Gajewski, John M. Kirkwood, Christine Gause, Lisa Chen, David R. Kaufman, Jeffrey Chou, F. Stephen Hodi News in immunotherapy O9 Two-year survival and safety update in patients (pts) with treatment-naïve advanced melanoma (MEL) receiving nivolumab (NIVO) or dacarbazine (DTIC) in CheckMate 066 Victoria Atkinson, Paolo A. Ascierto, Georgina V. Long, Benjamin Brady, Caroline Dutriaux, Michele Maio, Laurent Mortier, Jessica C. Hassel, Piotr Rutkowski, Catriona McNeil, Ewa Kalinka-Warzocha, Celeste Lebbé, Lars Ny, Matias Chacon, Paola Queirolo, Carmen Loquai, Parneet Cheema, Alfonso Berrocal, Karmele Mujika Eizmendi, Luis De La Cruz-Merino, Gil Bar-Sela, Christine Horak, Joel Jiang, Helene Hardy, Caroline Robert O10 Efficacy and safety of nivolumab (NIVO) in patients (pts) with advanced melanoma (MEL) who were treated beyond progression in CheckMate 066/067 Georgina V. Long, Jeffrey S. Weber, James Larkin, Victoria Atkinson, Jean-Jacques Grob, Reinhard Dummer, Caroline Robert, Ivan Marquez-Rodas, Catriona McNeil, Henrik Schmidt, Karen Briscoe, Jean-François Baurain, F. Stephen Hodi, Jedd D. Wolchok Tumor microenvironment and biomarkers O11 New biomarkers for response/resistance to BRAF inhibitor therapy in metastatic melanoma Rosamaria Pinto, Simona De Summa, Vito Michele Garrisi, Sabino Strippoli, Amalia Azzariti, Gabriella Guida, Michele Guida, Stefania Tommasi O12 Chemokine receptor patterns in lymphocytes mirror metastatic spreading in melanoma and response to ipilimumab Nicolas Jacquelot, David Enot, Caroline Flament, Jonathan M. Pitt, Nadège Vimond, Carolin Blattner, Takahiro Yamazaki, Maria-Paula Roberti, Marie Vetizou, Romain Daillere, Vichnou Poirier-Colame, Michaëla Semeraro, Anne Caignard, Craig L Slingluff Jr, Federica Sallusto, Sylvie Rusakiewicz, Benjamin Weide, Aurélien Marabelle, Holbrook Kohrt, Stéphane Dalle, Andréa Cavalcanti, Guido Kroemer, Anna Maria Di Giacomo, Michaele Maio, Phillip Wong, Jianda Yuan, Jedd Wolchok, Viktor Umansky, Alexander Eggermont, Laurence Zitvogel O13 Serum levels of PD1- and CD28-positive exosomes before Ipilimumab correlate with therapeutic response in metastatic melanoma patients Passarelli Anna, Tucci Marco, Stucci Stefania, Mannavola Francesco, Capone Mariaelena, Madonna Gabriele, Ascierto Paolo Antonio, Silvestris Franco O14 Immunological prognostic factors in stage III melanomas María Paula Roberti, Nicolas Jacquelot, David P Enot, Sylvie Rusakiewicz, Michaela Semeraro, Sarah Jégou, Camila Flores, Lieping Chen, Byoung S. Kwon, Ana Carrizossa Anderson, Caroline Robert, Christophe Borg, Benjamin Weide, François Aubin, Stéphane Dalle, Michele Maio, Jedd D. Wolchok, Holbrook Kohrt, Maha Ayyoub, Guido Kroemer, Aurélien Marabelle, Andréa Cavalcanti, Alexander Eggermont, Laurence Zitvogel POSTER PRESENTATIONS Molecular and immuno-advances P1 Human melanoma cells resistant to B-RAF and MEK inhibition exhibit mesenchymal-like features Anna Lisa De Presbiteris, Fabiola Gilda Cordaro, Rosa Camerlingo, Federica Fratangelo, Nicola Mozzillo, Giuseppe Pirozzi, Eduardo J. Patriarca, Paolo A. Ascierto, Emilia Caputo P2 Anti-proliferative and pro-apoptotic effect of ABT888 on melanoma cell lines and its potential role in the treatment of melanoma resistant to B-RAF inhibitors Federica Fratangelo, Rosa Camerlingo, Emilia Caputo, Maria Letizia Motti, Rosaria Falcone, Roberta Miceli, Mariaelena Capone, Gabriele Madonna, Domenico Mallardo, Maria Vincenza Carriero, Giuseppe Pirozzi and Paolo Antonio Ascierto P3 Involvement of the L-cysteine/CSE/H2S pathway in human melanoma progression Elisabetta Panza, Paola De Cicco, Chiara Armogida, Giuseppe Ercolano, Rosa Camerlingo, Giuseppe Pirozzi, Giosuè Scognamiglio, Gerardo Botti, Giuseppe Cirino, Angela Ianaro P4 Cancer stem cell antigen revealing pattern of antibody variable region genes were defined by immunoglobulin repertoire analysis in patients with malignant melanoma Beatrix Kotlan, Gabriella Liszkay, Miri Blank, Timea Balatoni, Judit Olasz, Emil Farkas, Andras Szollar, Akos Savolt, Maria Godeny, Orsolya Csuka, Szabolcs Horvath, Klara Eles, Yehuda Shoenfeld and Miklos Kasler P5 Upregulation of Neuregulin-1 expression is a hallmark of adaptive response to BRAF/MEK inhibitors in melanoma Debora Malpicci, Luigi Fattore, Susan Costantini, Francesca Capone, Paolo Antonio Ascierto, Rita Mancini, Gennaro Ciliberto P6 HuR positively regulates migration of HTB63 melanoma cells Farnaz Moradi, Pontus Berglund, Karin Leandersson, Rickard Linnskog, Tommy Andersson, Chandra Prakash Prasad P7 Prolyl 4- (C-P4H) hydroxylases have opposing effects in malignant melanoma: implication in prognosis and therapy Cristiana Lo Nigro, Laura Lattanzio, Hexiao Wang, Charlotte Proby, Nelofer Syed, Marcella Occelli, Carolina Cauchi, Marco Merlano, Catherine Harwood, Alastair Thompson, Tim Crook P8 Urokinase receptor antagonists: novel agents for the treatment of melanoma Maria Letizia Motti, Katia Bifulco, Vincenzo Ingangi, Michele Minopoli, Concetta Ragone, Federica Fratangelo, Antonello Pessi, Gennaro Ciliberto, Paolo Antonio Ascierto, Maria Vincenza Carriero P9 Exosomes released by melanoma cell lines enhance chemotaxis of primary tumor cells Francesco Mannavola, Stella D’Oronzo, Claudia Felici, Marco Tucci, Antonio Doronzo, Franco Silvestris P10 New insights in mitochondrial metabolic reprogramming in melanoma Anna Ferretta, Gabriella Guida, Stefania Guida, Imma Maida, Tiziana Cocco, Sabino Strippoli, Stefania Tommasi, Amalia Azzariti, Michele Guida P11 Lenalidomide restrains the proliferation in melanoma cells through a negative regulation of their cell cycle Stella D’Oronzo, Anna Passarelli, Claudia Felici, Marco Tucci, Davide Quaresmini, Franco Silvestris Combination therapies P12 Chemoimmunotherapy elicits polyfunctional anti-tumor CD8 + T cells depending on the activation of an AKT pathway sustained by ICOS Ornella Franzese, Belinda Palermo, Cosmo Di Donna, Isabella Sperduti, MariaLaura Foddai, Helena Stabile, Angela Gismondi, Angela Santoni, Paola Nisticò P13 Favourable toxicity profile of combined BRAF and MEK inhibitors in metastatic melanoma patients Andrea P. Sponghini, Francesca Platini, Elena Marra, David Rondonotti, Oscar Alabiso, Maria T. Fierro, Paola Savoia, Florian Stratica, Pietro Quaglino P14 Electrothermal bipolar vessel sealing system dissection reduces seroma output or time to drain removal following axillary and ilio-inguinal node dissection in melanoma patients: a pilot study Di Monta Gianluca, Caracò Corrado, Di Marzo Massimiliano, Marone Ugo, Di Cecilia Maria Luisa, Mozzillo Nicola News in immunotherapy P15 Clinical and immunological response to ipilimumab in a metastatic melanoma patient with HIV infection Francesco Sabbatino, Celeste Fusciello1, Antonio Marra, Rosario Guarrasi, Carlo Baldi, Rosa Russo, Di Giulio Giovanni, Vincenzo Faiola, Pio Zeppa, Stefano Pepe P16 Immunotherapy and hypophysitis: a case report Elisabetta Gambale, Consiglia Carella, Alessandra Di Paolo, Michele De Tursi Tumor microenvironment and biomarkers P17 New immuno- histochemical markers for the differential diagnosis of atypical melanocytic lesions with uncertain malignant potential Laura Marra, Giosuè Scognamiglio, Monica Cantile, Margherita Cerrone, Fara De Murtas, Valeria Sorrentino, Anna Maria Anniciello, Gerardo Botti P18 Utility of simultaneous measurement of three serum tumor markers in melanoma patients Angela Sandru, Silviu Voinea, Eugenia Panaitescu, Madalina Bolovan, Adina Stanciu, Sabin Cinca P19 The significance of various cut-off levels of melanoma inhibitory activity in evaluation of cutaneous melanoma patients Angela Sandru, Silviu Voinea, Eugenia Panaitescu, Madalina Bolovan, Adina Stanciu, Sabin Cinca P20 The long noncoding RNA HOTAIR is associated to metastatic progression of melanoma and it can be identified in the blood of patients with advanced disease Chiara Botti, Giosuè Scognamiglio, Laura Marra, Gabriella Aquino, Rosaria Falcone, Annamaria Anniciello, Paolo Antonio Ascierto, Gerardo Botti, Monica Cantile Other P21 The effect of Sentinel Lymph Node Biopsy in melanoma mortality: timing of dissection Cristina Fortes, Simona Mastroeni, Alessio Caggiati, Francesca Passarelli, Alba Zappalà, Maria Capuano, Riccardo Bono, Maurizio Nudo, Claudia Marino, Paola Michelozzi P22 Epidemiological survey on related psychopathology in melanoma Valeria De Biasio, Vincenzo C. Battarra IMMUNOTHERAPY BRIDGE KEYNOTE SPEAKER PRESENTATIONS Immunotherapy beyond melanoma K19 Predictor of response to radiation and immunotherapy Silvia Formenti K20 Response and resistance to PD-1 pathway blockade: clues from the tumor microenvironment Maria Libera Ascierto, Tracee L. McMiller, Alan E. Berger, Ludmila Danilova, Robert A. Anders, George J. Netto, Haiying Xu, Theresa S. Pritchard, Jinshui Fan, Chris Cheadle, Leslie Cope, Charles G. Drake, Drew M. Pardoll, Janis M. Taube and Suzanne L. Topalian K21 Combination immunotherapy with autologous stem cell transplantation, protein immunization, and PBMC reinfusion in myeloma patients Sacha Gnjatic, Sarah Nataraj, Naoko Imai, Adeeb Rahman, Achim A. Jungbluth, Linda Pan, Ralph Venhaus, Andrew Park, Frédéric F. Lehmann, Nikoletta Lendvai, Adam D. Cohen, and Hearn J. Cho K22 Anti-cancer immunity despite T cell “exhaustion” Speiser Daniel Immunotherapy in oncology (I-O): data from clinical trial K23 The Checkpoint Inhibitors for the Treatment of Metastatic Non-small Cell Lung Cancer (NSCLC) Vera Hirsh

Published
2016

30. Abstract A040: The low antitumor functionality of PD1-positive gp100-specific CD8+ T cell clones isolated from melanoma patients correlates with the presence of CD28 co-stimulatory molecule

Author

Palermo, Belinda, primary, Franzese, Ornella, additional, Donna, Cosmo Di, additional, Panetta, Mariangela, additional, Sperduti, Isabella, additional, Soriani, Antonella, additional, Foddai, Maria Laura, additional, Santoni, Angela, additional, and Nisticò, Paola, additional

Published
2016
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33. Abstract A003: Polyfunctional antitumor CD8 T cells obtained from a broad repertoire elicited by chemo-immunotherapy and preventing melanoma relapse depends on the activation of an AKT pathway sustained by ICOS

Author

Franzese, Ornella, primary, Palermo, Belinda, additional, Donna, Cosmo Di, additional, Sperduti, Isabella, additional, Panetta, Mariangela, additional, Foddai, Maria Laura, additional, Santoni, Angela, additional, and Nisticò, Paola, additional

Published
2016
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34. Exogenous Control of the Expression of Group I CD1 Molecules Competent for Presentation of Microbial Nonpeptide Antigens to Human T Lymphocytes

Author

Aquino, Angelo, Graziani, Grazia, Franzese, Ornella, Prete, Salvatore P., Bonmassar, Enzo, Bonmassar, Laura, and D'Atri, Stefania

Subjects
Article Subject, parasitic diseases, hemic and immune systems, lipids (amino acids, peptides, and proteins), chemical and pharmacologic phenomena, complex mixtures
Abstract

Group I CD1 (CD1a, CD1b, and CD1c) glycoproteins expressed on immature and mature dendritic cells present nonpeptide antigens (i.e., lipid or glycolipid molecules mainly of microbial origin) to T cells. Cytotoxic CD1-restricted T lymphocytes recognizing mycobacterial lipid antigens were found in tuberculosis patients. However, thanks to a complex interplay between mycobacteria and CD1 system, M. tuberculosis possesses a successful tactic based, at least in part, on CD1 downregulation to evade CD1-dependent immunity. On the ground of these findings, it is reasonable to hypothesize that modulation of CD1 protein expression by chemical, biological, or infectious agents could influence host's immune reactivity against M. tuberculosis-associated lipids, possibly affecting antitubercular resistance. This scenario prompted us to perform a detailed analysis of the literature concerning the effect of external agents on Group I CD1 expression in order to obtain valuable information on the possible strategies to be adopted for driving properly CD1-dependent immune functions in human pathology and in particular, in human tuberculosis.

Published
2011
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35. Hippo Pathway Effectors Control Cardiac Progenitor Cell Fate by Acting as Dynamic Sensors of Substrate Mechanics and Nanostructure

Author

Mosqueira, Diogo, primary, Pagliari, Stefania, additional, Uto, Koichiro, additional, Ebara, Mitsuhiro, additional, Romanazzo, Sara, additional, Escobedo-Lucea, Carmen, additional, Nakanishi, Jun, additional, Taniguchi, Akiyoshi, additional, Franzese, Ornella, additional, Di Nardo, Paolo, additional, Goumans, Marie José, additional, Traversa, Enrico, additional, Pinto-do-Ó, Perpetua, additional, Aoyagi, Takao, additional, and Forte, Giancarlo, additional

Published
2014
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39. Abstract 4406: Clinical efficacious combined chemo/immunotherapy differently activates AKT pathway and functionality of gp100 and Melan-A specific T cell clones

Author

Palermo, Belinda, primary, Donna, Cosmo Di, additional, Franzese, Ornella, additional, Bello, Duilia Del, additional, Gualtieri, Novella, additional, Imberti, Luisa, additional, Nuzzo, Carmen, additional, Proietti, Enrico, additional, Catricalà, Caterina, additional, Ferraresi, Virginia, additional, and Nisticò, Paola, additional

Published
2012
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40. Combination of DTIC and peptide-vaccination elicit a renewal of high-avidity late-differentiated T-cell clones in melanoma patients (156.6)

Author

Palermo, Belinda, primary, Del Bello, Duilia, additional, Franzese, Ornella, additional, Di Donna, Cosmo, additional, Gualtieri, Novella, additional, Nuzzo, Carmen, additional, Proietti, Enrico, additional, Catricalà, Caterina, additional, Ferraresi, Virginia, additional, and Nistico, Paola, additional

Published
2011
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41. The Loss of Telomerase Activity in Highly Differentiated CD8+CD28−CD27− T Cells Is Associated with Decreased Akt (Ser473) Phosphorylation

Author

Plunkett, Fiona J., primary, Franzese, Ornella, additional, Finney, Helene M., additional, Fletcher, Jean M., additional, Belaramani, Lavina L., additional, Salmon, Mike, additional, Dokal, Inderjeet, additional, Webster, David, additional, Lawson, Alastair D. G., additional, and Akbar, Arne N., additional

Published
2007
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43. The impact of telomere erosion on memory CD8+ T cells in patients with X-linked lymphoproliferative syndrome

Author

Plunkett, Fiona J., primary, Franzese, Ornella, additional, Belaramani, Lavina L., additional, Fletcher, Jean M., additional, Gilmour, Kimberly C., additional, Sharifi, Reza, additional, Khan, Naeem, additional, Hislop, Andrew D., additional, Cara, Andrea, additional, Salmon, Mike, additional, Gaspar, H. Bobby, additional, Rustin, Malcom H.A., additional, Webster, David, additional, and Akbar, Arne N., additional

Published
2005
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45. Evaluation of Telomerase Activity in Nasal Polyps

Author

Bruno, Ernesto, primary, Bonmassar, Enzo, additional, Di Girolamo, Stefano, additional, Adamo, Riccardo, additional, Alessandrini, Marco, additional, Ottaviani, Fabrizio, additional, Rosati, Faustino, additional, and Franzese, Ornella, additional

Published
2004
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