Interleukin-12 (IL-12), a powerful type 1 pro-inflammatory cytokine, demonstrates significant antitumor properties across numerous preclinical tumor models. However, the impressive antitumor efficacy ...demonstrated by IL-12 in preclinical studies has not been effectively reproduced in clinical researches. Clinical studies utilizing IL-12 as a treatment predominantly have shown limited efficacy in achieving sustained antitumor responses and are often accompanied by significant toxicities. Nevertheless, IL-12’s pleiotropic antitumor activity still predicts a great promising future in cancer therapy, attracting enormous cancer researchers. Efforts are underway to enhance the local accumulation of IL-12 within the tumor microenvironment while minimizing systemic exposure. In preclinical studies, diverse IL-12 delivery systems, from fusion proteins to mRNA encapsulated in nanoparticles, have demonstrated robust antitumor effects with reduced toxicity. Several IL-12 delivery approaches have recently entered the clinical stage. In this review, we mainly discuss the development of nanomedicine-associated delivery mechanisms for IL-12 in cancer therapy, emphasizing advantageous approaches to harness IL-12's antitumor properties and mitigate its adverse side effects.
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•IL-12’s pleiotropic antitumor activity indicates its promising future in cancer immunotherapy.•Nanotechnology enhances local retention of IL-12 within tumor while minimizing systemic exposure.•Recent advances in clinical translation highlight the advantages of mRNA-based nanomedicine for IL-12 delivery.
Cancer immunotherapy and tumor microenvironment have been at the forefront of research over the past decades. Targeting immune checkpoints especially programmed death 1 (PD-1)/programmed death ligand ...1 (PD-L1) has made a breakthrough in treating advanced malignancies. However, the low response rate brings a daunting challenge, changing the focus to dig deeply into the tumor microenvironment for alternative therapeutic targets. Strikingly, the inhibitory immune checkpoint lymphocyte activation gene-3 (LAG-3) holds considerable potential. LAG-3 suppresses T cells activation and cytokines secretion, thereby ensuring immune homeostasis. It exerts differential inhibitory impacts on various types of lymphocytes and shows a remarkable synergy with PD-1 to inhibit immune responses. Targeting LAG-3 immunotherapy is moving forward in active clinical trials, and combination immunotherapy of anti-LAG-3 and anti-PD-1 has shown exciting efficacy in fighting PD-1 resistance. Herein, we shed light on the significance of LAG-3 in the tumor microenvironment, highlight its role to regulate different lymphocytes, interplay with other immune checkpoints especially PD-1, and emphasize new advances in LAG-3-targeted immunotherapy.
The emergence of programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1)–targeted therapy has demonstrated the importance of the PD-L1: PD-1 interaction in inhibiting anticancer T-cell immunity ...in multiple human cancers, generating durable responses and extended overall survival. However, not all patients treated with PD-L1/PD-1–targeted therapy experience tumor shrinkage, durable responses, or prolonged survival. To extend such benefits to more cancer patients, it is necessary to understand why some patients experience primary or secondary immune escape, in which the immune response is incapable of eradicating all cancer cells. Understanding immune escape from PD-L1/PD-1–targeted therapy will be important to the development of rational immune-combination therapy and predictive diagnostics and to the identification of novel immune targets. Factors that likely relate to immune escape include the lack of strong cancer antigens or epitopes recognized by T cells, minimal activation of cancer-specific T cells, poor infiltration of T cells into tumors, downregulation of the major histocompatibility complex on cancer cells, and immunosuppressive factors and cells in the tumor microenvironment. Precisely identifying and understanding these mechanisms of immune escape in individual cancer patients will allow for personalized cancer immunotherapy, in which monotherapy and combination immunotherapy are chosen based on the presence of specific immune biology. This approach may enable treatment with immunotherapy without inducing immune escape, resulting in a larger proportion of patients obtaining clinical benefit.
Regulatory T cells (Tregs) are a barrier to anti-tumor immunity. Neuropilin-1 (Nrp1) is required to maintain intratumoral Treg stability and function but is dispensable for peripheral immune ...tolerance. Treg-restricted Nrp1 deletion results in profound tumor resistance due to Treg functional fragility. Thus, identifying the basis for Nrp1 dependency and the key drivers of Treg fragility could help to improve immunotherapy for human cancer. We show that a high percentage of intratumoral NRP1+ Tregs correlates with poor prognosis in melanoma and head and neck squamous cell carcinoma. Using a mouse model of melanoma where Nrp1-deficient (Nrp1–/–) and wild-type (Nrp1+/+) Tregs can be assessed in a competitive environment, we find that a high proportion of intratumoral Nrp1–/– Tregs produce interferon-γ (IFNγ), which drives the fragility of surrounding wild-type Tregs, boosts anti-tumor immunity, and facilitates tumor clearance. We also show that IFNγ-induced Treg fragility is required for response to anti-PD1, suggesting that cancer therapies promoting Treg fragility may be efficacious.
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•Increased percentage of human NRP1+ intratumoral Tregs correlates with poor prognosis•Nrp1-deficient Tregs undermine the function of wild-type Tregs via IFNγ•Hypoxia may drive IFNγ-induced Treg fragility via Hif1α in the tumor microenvironment•IFNγ-mediated Treg functional fragility is required for response to PD1 blockade
Driving Treg fragility in the tumor microenvironment is critical for the efficacy of cancer checkpoint blockade therapy.
The tumor microenvironment is profoundly immunosuppressive. We show that multiple tumor types create intratumoral immune suppression driven by a specialized form of regulatory T cell (Treg) ...activation dependent on the PTEN (phosphatase and tensin homolog) lipid phosphatase. PTEN acted to stabilize Tregs in tumors, preventing them from reprogramming into inflammatory effector cells. In mice with a Treg-specific deletion of PTEN, tumors grew slowly, were inflamed, and could not create an immunosuppressive tumor microenvironment. In normal mice, exposure to apoptotic tumor cells rapidly elicited PTEN-expressing Tregs, and PTEN-deficient mice were unable to maintain tolerance to apoptotic cells. In wild-type mice with large established tumors, pharmacologic inhibition of PTEN after chemotherapy or immunotherapy profoundly reconfigured the tumor microenvironment, changing it from a suppressive to an inflammatory milieu, and tumors underwent rapid regression. Thus, the immunosuppressive milieu in tumors must be actively maintained, and tumors become susceptible to immune attack if the PTEN pathway in Tregs is disrupted.
Brain cancers, particularly glioblastoma multiforme (GBM), are challenging health issues with frequent unmet aspects. Today, discovering safe and effective therapeutic modalities for brain tumors is ...among the top research interests. Immunotherapy is an emerging area of investigation in cancer treatment. Since immune checkpoints play fundamental roles in repressing anti-cancer immunity, diverse immune checkpoint inhibitors (ICIs) have been developed, and some monoclonal antibodies have been approved clinically for particular cancers; nevertheless, there are significant concerns regarding their efficacy and safety in brain tumors. Among the various tools to modify the immune checkpoints, phytochemicals show good effectiveness and excellent safety, making them suitable candidates for developing better ICIs. Phytochemicals regulate multiple immunological checkpoint-related signaling pathways in cancer biology; however, their efficacy for clinical cancer immunotherapy remains to be established. Here, we discussed the involvement of immune checkpoints in cancer pathology and summarized recent advancements in applying phytochemicals in modulating immune checkpoints in brain tumors to highlight the state-of-the-art and give constructive prospects for future research.
•Brain cancers, particularly glioblastoma multiforme (GBM) are challenging health issues.•Immunotherapy is an emerging area of investigation in cancer treatment.•Phytochemicals show good effectiveness and making them suitable to develop immune checkpoint inhibitors (ICIs).•We discussed the involvement of immune checkpoints in cancer pathology.•We also summarized the application of phytochemicals in modulating immune checkpoints in brain tumors.
Cancer immunotherapy has transformed the treatment landscape for numerous malignancies and is emerging as an increasingly revolutionary and promising approach for cancer treatment.Clustered regularly ...interspaced palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) screening, a potent tool for unbiased functional genomic screening, has unveiled novel molecular targets for cancer immunotherapy.CRISPR/Cas9 screening facilitates the identification of targets in both cancer cells and immune cells, including T and natural killer cells.Various CRISPR screening methods such as in vitro and in vivo screening, along with diverse techniques including CRISPR-ko, CRISPRi, and CRISPRa screening, are utilized for target identification across various cancer models.In vivo CRISPR screening replicates human cancer by preserving the native microenvironment and facilitating high-throughput analysis of intricate cancer processes.
Clustered regularly interspaced palindromic repeats (CRISPR)-based technology, a powerful toolset for the unbiased functional genomic screening of biological processes, has facilitated several scientific breakthroughs in the biomedical field. Cancer immunotherapy has advanced the treatment of numerous malignancies that previously had restricted treatment options or unfavorable outcomes. In the realm of cancer immunotherapy, the application of CRISPR/CRISPR-associated protein 9 (Cas9)-based genetic perturbation screening has enabled the identification of genes, biomarkers, and signaling pathways that govern various cancer immunoreactivities, as well as the development of effective immunotherapeutic targets. In this review, we summarize the advances in CRISPR/Cas9-based screening for cancer immunotherapy and outline the immunotherapeutic targets identified via CRISPR screening based on cancer-type classification.
Clustered regularly interspaced palindromic repeats (CRISPR)-based technology, a powerful toolset for the unbiased functional genomic screening of biological processes, has facilitated several scientific breakthroughs in the biomedical field. Cancer immunotherapy has advanced the treatment of numerous malignancies that previously had restricted treatment options or unfavorable outcomes. In the realm of cancer immunotherapy, the application of CRISPR/CRISPR-associated protein 9 (Cas9)-based genetic perturbation screening has enabled the identification of genes, biomarkers, and signaling pathways that govern various cancer immunoreactivities, as well as the development of effective immunotherapeutic targets. In this review, we summarize the advances in CRISPR/Cas9-based screening for cancer immunotherapy and outline the immunotherapeutic targets identified via CRISPR screening based on cancer-type classification.
Correction to: J Transl Med (2020) 18:405 https://doi.org/10.1186/s12967-020-02573-9 Following publication of the original article 1 the authors identified that the collaborators of the TOCIVID-19 ...investigators, Italy were only available in the supplementary file. The original article has been updated so that the collaborators are correctly acknowledged. For clarity, all collaborators are listed in this correction article. Acknowledgement List of participating centres and Co-Investigators TOCIVID-19 Investigators * Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli—Clinical Trials Unit: Francesco Perrone, Maria Carmela Piccirillo, Clorinda Schettino, Adriano Gravina, Piera Gargiulo, Claudia Cardone, Laura Arenare; Melanoma And Cancer Immunotherapy And Developmental Therapeutics Unit: Paolo Antonio Ascierto, Maria Grazia Vitale, Claudia Trojaniello, Marco Palla; Direction: Attilio Antonio Montano Bianchi, Gerardo Botti, Gianfranco De Feo, Leonardo Miscio. * Università degli Studi della Campania Luigi Vanvitelli, Dipartimento di Salute Mentale e Medicina Preventiva; Ciro Gallo, Paolo Chiodini. * IRCCS Policlinico San Donato—Milano: Laurenzia Ferraris, Massimiliano M. Marrocco-Trischitta, Marco Froldi, Lorenzo Menicanti, Maria Teresa Cuppone, Giulia Gobbo, Chiara Baldessari, Vincenzo Valenti, Serenella Castelvecchio, Federica Poli, Francesca Giacomazzi, Rosangela Piccinni, Maria Laura Annnunziata, Andrea Biondi, Cecilia Bussolari, Manuel Mazzoleni, Andrea Giachi, Annalisa Filtz, Arianna Manini, Enrico Poletti, Federico Masserini, Francesco Conforti, Gianfranco Gaudiano, Vittoria Favero, Alice Moroni, Tommaso Viva, Fabiana Fancoli, Davide Ferrari, Dario Niro, Marco Resta, Andrea Ballotta, Marco Dei Poli, Marco Ranucci. * ASST Papa Giovanni XXIII—Bergamo: Diego Ripamonti, Francesca Binda, Alessandra Tebaldi, Giuseppe Gritti, Luisa Pasulo, Leonardo Gaglio, Roberto Del Fabbro, Leonardo Alborghetti. * ASST Monza—Monza: Paolo Bonfanti, Nicola Squillace, Giulia Giustinetti, Paola Columpsi, Marina Cazzaniga, Serena Capici, Luca Sala, Riccardo Di Sciacca, Giacomo Mosca, Maria Rosa Pirozzi. * ASST degli Spedali Civili di Brescia e Università di Brescia—Brescia: Francesco Castelli, Maria Lorenza Muiesan, Franco Franceschini, Aldo Roccaro, Massimo Salvetti, Anna Paini, Luciano Corda, Chiara Ricci, Lina Tomasoni, Paola Nasta, Silvia Lorenzotti, Silvia Odolini, Emanuele Focà, Eugenia Quiros Roldan, Marco Metra, Stefano Magrini, Paolo Borghetti, Nicola Latronico, Simone Piva, Matteo Filippini, Gabriele Tomasoni, Francesco Zuccalà, Sergio Cattaneo, Francesco Scolari, Nicola Bossini, Mario Gaggiotti, Martina Properzi. * Ospedale Santa Maria Goretti—Latina: Miriam Lichtner, Emanuela Del Giudice, Raffaella Marocco, Anna Carraro, Cosmo Del Borgo, Raffaella Marocco, Valeria Belvisi, Tiziana Tieghi, Margherita De Masi, Paola Zuccalà, Paolo Fabietti, Angelo Vetica, Vito Sante Mercurio, Anna Carraro, Laura Fondaco, Blerta Kertusha, Ambrogio Curtolo, Emanuela Del Giudice, Riccardo Lubrano, Maria Gioconda Zotti, Antonella Puorto, Marcello Ciuffreda, Antonella Sarni, Gabriella Monteforte, Domenico Romeo, Emanuela Viola, Carla Damiani, Antonietta Barone, Barbara Mantovani, Daniela Di Sanzo, Vincenzo Gentili, Massimo Carletti, Massimo Aiuti, Andrea Gallo, Piero Giuseppe Meliante, Salvatore Martellucci, Oliviero Riggio, Vincenzo Cardinale, Lorenzo Ridola, Maria Consiglia Bragazzi, Stefania Gioia, Emiliano Valenzi, Camilla Graziosi, Niccolò Bina, Martina Fasolo, Silvano Ricci, Maria Teresa Gioacchini, Antonella Lucci, Luisella Corso, Daniela Tornese, Parni Nijhawan, Francesco Equitani, Carmine Cosentino, Marcello Palladino, Frida Leonetti, Gaetano Leto, Camillo Gnessi, Giuseppe Campagna, Roberto Cesareo, Francesca Marrocco, Giuseppe Straface, Alessandra Mecozzi, Lidia Cerbo, Valentina Isgrò, Sergio Parrocchia, Giuseppe Visconti, Giorgio Casati. * AOU di Parma—Parma: Carlo Calzetti, Alarico Ariani, Lorenzo Donghi. * AOUI di Verona—Verona: Nicola Duccio Salerno, Evelina Tacconelli, Marco Bertoldi, Paolo Cattaneo, Lorenza Lambertenghi, Leonardo Motta, Luca Omega. * Humanitas Gavazzeni—Bergamo: Giovanni Albano. * AORN Dei Colli—Napoli: Roberto Parrella, Fiorentino Fraganza, Luigi Atripaldi, Vincenzo Montesarchio, Francesco Scarano, Annunziata De Rosa, Amalia Buglione, Sabrina Lavoretano, Gianfranco Gaglione, Mario De Marco, Vincenzo Sangiovanni, Francesco Maria Fusco, Rosaria Viglietti, Elio Manzillo, Carolina Rescigno, Raffaella Pisapia, Giulia Plamieri, Alberto Maraolo, Giosuè Calabria, Mario Catalano, Giuseppe Fiorentino, Anna Annunziata, Giorgio Polistina, Pasquale Imitazione, Mariano Mollica, Vincenzo Esposito, Maurizio D’Abraccio, Rodolfo Punzi, Vincenzo Bianco, Costanza Sbreglia. * Azienda Ospedaliera Umberto I—Siracusa: Rosa Fontana Del Vecchio, Alessandro Bordonali, Antonina Franco. * Arcispedale Santa Maria Nuova IRCCS—Reggio Emilia: Carlo Salvarani, Marco Massari, Giovanni Dolci, Pierpaolo Salsi, Matteo Fontana. * ASST di Cremona—Cremona: Giuseppe Virzì, Calderone Ornella, Alfredo Molteni. * Azienda Ospedaliera San Salvatore—Pesaro: Silvia Gennarini, Umberto Gnudi, Maria Anastasia Ricci, Giancarlo Titolo, Giulio Mensi, Pietro Vuotto, Beatrice Gasperini, Mauro Mancini, Zeno Pasquini. * Ospedale Bassini—Cinisello Balsamo: Paolo Spanu, Stefano Clementi, Simona Pierini, Daniela Bokor, Daniela Gori, Morena Ciofetti, Marina Caimi, Laura Bettazzi, Elisabetta Allevi, Silvia Furiani, Chiara Capitanio, Bernardino Mastropasqua, Claudio Fara, Grazia Pulitanò, Jun Sebastian Matsuno, Francesca Della Porta, Viola Dolfini, Nebiat Balei Beyene. * ASST Degli Spedali Civili Di Brescia—Brescia: Michela Bezzi, Mauro Novali. * AOU di Bologna—Bologna: Pierluigi Viale, Sara Tedeschi, Renato Pascale. * Policlinico S. Matteo—Pavia: Raffaele Bruno, Alessandro Di Filippo, Michele Sachs, Tiberio Oggionni, Michele Di Stefano, Caterina Mengoli. * Ospedale di Conegliano—Conegliano: Cesarina Facchini, De Nardo Daniele. * Azienda Ospedaliera San Salvatore—Pesaro: Gabriele Frausini, Luciano Mucci, Silvia Tedesco, Rita Girolimetti, Elena Manfredini, Anna Maria Di Carlo, Emma Espinosa, Donatella Dennetta. * AOU di Parma—Parma: Andrea Ticinesi, Tiziana Meschi, Antonio Nouvenne. * Azienda Ospedaliera Ordine Mauriziano—Torino: Norbiato Claudio, Francesco Vitale, Marta Saracco. * Ospedale Guglielmo Da Saliceto—Piacenza: Mauro Codeluppi, Elisa Fronti, Patrizia Ferrante. * Ospedale di Fermo—Fermo: Giorgio Amadio Nespola. * AOU di Perugia—Perugia: Daniela Francisci, Andrea Tosti. * Casa Sollievo Della Sofferenza—San Giovanni Rotondo: Cristiano Matteo Carbonelli, Antonio Greco, Maria Giulia Tinti. * Fondazione Poliambulanza Istituto Ospedaliero—Brescia: Roberto Stellini, Camilla Appiani, Piera Reghenzi. * Ospedale Morgagni-Pierantoni—Forlì: Venerino Poletti, Claudia Ravaglia. * Ospedale Area Aretina Nord—Arezzo: Danilo Tacconi, Costanza Malcontenti. * AOU “Maggiore della Carità”—Novara: Pier Paolo Sainaghi, Raffaella Landi, Veronica Vassia, Eleonora Rizzi, Mattia Bellan, Antonella Rossati, Luigi Castello * Policlinico Umberto I—Roma: Claudio Maria Mastroianni, Gianluca Russo. * Presidio Ospedaliero di Jesolo—Jesolo: Toffoletto Fabio, Francesco Saverio Serino, Lucio Brollo, Elena Momesso, Maria Luisa Turati. * ASST Santi Paolo e Carlo—Milano: Antonella D'arminio Monforte, Giulia Marchetti. * Ospedale Civile di Guastalla—Guastalla: Fabrizio Boni, Elisabetta Teopompi, Chiara Trenti, Luca Boracchia, Enrica Minelli, Matteo Fontana, Giulia Ghidoni, Anaflorina Matei, Andrea Caruso. * AO Ospedali Riuniti Villa Sofia e Cervello—Palermo: Giuseppe Arcoleo, Gaetana Camarda, Filippo Catalano, Mario Spatafora. * Ospedale Sacra Famiglia, Fatebenefratelli—Erba: Donato Bettega. * AOU Policlinico Tor Vergata—Roma: Massimo Andreoni, Elisabetta Teti, Loredana Sarmati, Andrea Di Lorenzo, Mariagrazia Celeste. * Ospedali Riuniti Padova Sud—Padova: Fabio Baratto, Jacopo Monticelli, Pietro Criveller. * Ospedale San Paolo—Savona: Antonini Andrea, Anselmo, Riccio. * ASST Spedali Civili Di Brescia—Brescia: Maurizio Castellano, Carlo Cappelli, Federica Corvini, Barbara Zanini. * ASST Spedali Civili Di Brescia, Presidio Ospedaliero Gardone—Brescia: Massimo Crippa, Maurizio Ronconi, Raffaella Costa, Silvia Casella, Loretta Brentana. * Ospedale Civile e Ospedale Dell'Angelo—Mestre: Livio Bernardi, Andrea Frascati, Sandro Panese, Fabio Presotto, Lucio Michieletto, Cristina Bernardi. * Ospedale Santa Maria Delle Croci—Ravenna: Maurizio Fusar. * Presidio Ospedaliero di Cesena—Cesena: Vanni Agnoletti, Martina Farina, Russo. * AOU Careggi—Firenze: Federico Lavorini, Roberta Ginanni. * Istituto Nazionale Malattie Infettive INMI L. Spallanzani, IRCCS—Roma: Fabrizio Palmieri, Silvia Mosti. * Casa Di Cura Beato Palazzolo—Bergamo: Angelo Amaglio, Alessandra Cattaneo. * Istituto Clinico S. Ambrogio Spa—Milano: Silvia Cirri, Andrea Montisci, Chiara Gallazzi, Daniele Cosseta, Barabara Baronio, Lorenzo Rampa. * AO Sant’Anna e San Sebastiano—Caserta: Paolo Maggi, Vincenzo Messina. * Arcispedale Santa Maria Nuova IRCCS—Reggio Emilia: Emanuele Alberto Negri, Chiara Trenti. * Ospedale Generale Provinciale—Macerata: Marialma Berlendis, Maria Cecilia Sabatti. * Azienda Ospedaliera S. Maria—Terni: Michele Palumbo. * ASST Ovest Milanese—Milano: Antonino Mazzone, Paola Faggioli. * Ospedale Bellaria—Bologna: Linda Bussini, Giacomo Fornaro, Francesca Volpato. * Ospedale Maria Vittoria—Torino: Daniele Imperiale, Emilpaolo Manno, Enrico Ferreri, Domenico Martelli, Andrea Verhovez, Silvia Giorgis, Luciana Faccio, Rachele Delli Quadri, Cristina Negro. * Ospedale Giovanni Bosco—Torino: Marcella Converso, Francesca Bosco. * ASST Desenzano Del Garda—Gavardo: Silvia Amadasi, Paolo Prandini, Silvia Cocchi. * Azienda ULSS 6—Vicenza: Vinicio Manfrin, Veronica Del Punta. * PO Sant’Elia—Caltanissetta: Giovanni Mazzola, Giuseppe Sportato. * Ospedale Ca’ Foncello—Treviso: Micaela Romagnoli. * Ospedale Infermi—Rimini: Francesco Cristini
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