{"id":{"repo_id":"milano","oai_identifier":"oai:air.unimi.it:2434/958937"},"canonical_url":"https://search.dev.ndltd.org/etd/milano/oai:air.unimi.it:2434/958937","repository":{"repo_id":"milano","name":"Università degli Studi di Milano","base_url":"https://air.unimi.it/oai/request"},"display":{"title":"LINOLEIC ACID UNLEASHES THE ANTI-TUMOR POTENTIAL OF CD8 T CELLS BY PROMOTING METABOLIC REPROGRAMMING","abstract":"T cell therapy (ACT) has achieved unprecedented clinical results in the treatment of cancer, but scarce intra-tumor infiltration, persistence and function of adoptively transferred T cells limit its efficacy, especially in solid tumors. Metabolic constraints imposed by the tumor microenvironment (TME) greatly influence the success of immune-based therapies. A common metabolic alteration in the TME is lipid accumulation, a feature often associated with defective anti-tumor responses. However, whether all lipids are detrimental to T cell functions and how they regulate different fate decisions remains poorly understood. Here, we identified Linoleic Acid (LA) as a major positive regulator of CTL activity. LA endows CTL with improved metabolic fitness and redirects them away from exhaustion and towards a memory-like phenotype with superior effector functions. Mechanistically, LA treatment fosters the formation of ER-mitochondria contacts (MERC) and mitochondrial-associated-membranes (MAMs), which in turn promotes calcium (Ca2+) signaling, mitochondrial energetics, and CTL effector functions. As a result, LA-instructed CD8+ T cells mediate superior control towards different tumor types both in vitro and in vivo following ACT on mouse models, overcoming the hustle of a highly immunosuppressive TME. Our results pave the way for a new generation of adoptive T cell-based therapies, where LA can be used during ex vivo CAR- and TCR- T cell manufacturing as a novel approach to achieve metabolic reprogramming and long-term functionality, broadening the therapeutic efficacy of ACT to a wide range of malignancies.","abstract_html":"T cell therapy (ACT) has achieved unprecedented clinical results in the treatment of cancer, but scarce intra-tumor infiltration, persistence and function of adoptively transferred T cells limit its efficacy, especially in solid tumors. Metabolic constraints imposed by the tumor microenvironment (TME) greatly influence the success of immune-based therapies. A common metabolic alteration in the TME is lipid accumulation, a feature often associated with defective anti-tumor responses. However, whether all lipids are detrimental to T cell functions and how they regulate different fate decisions remains poorly understood. Here, we identified Linoleic Acid (LA) as a major positive regulator of CTL activity. LA endows CTL with improved metabolic fitness and redirects them away from exhaustion and towards a memory-like phenotype with superior effector functions. Mechanistically, LA treatment fosters the formation of ER-mitochondria contacts (MERC) and mitochondrial-associated-membranes (MAMs), which in turn promotes calcium (Ca2+) signaling, mitochondrial energetics, and CTL effector functions. As a result, LA-instructed CD8+ T cells mediate superior control towards different tumor types both in vitro and in vivo following ACT on mouse models, overcoming the hustle of a highly immunosuppressive TME. Our results pave the way for a new generation of adoptive T cell-based therapies, where LA can be used during ex vivo CAR- and TCR- T cell manufacturing as a novel approach to achieve metabolic reprogramming and long-term functionality, broadening the therapeutic efficacy of ACT to a wide range of malignancies.","abstract_has_math":false,"creators":["NAVA LAUSON, CARINA B."],"institution":"Università degli Studi di Milano","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["tutor: T. Manzo ; co-tutor: S. Santaguida ; phd coordinator: S. Minucci ; curators: B. Amati","C. Vernieri","D. Cantrell","P. Ho","C.B. NAVA LAUSON","MINUCCI, SAVERIO"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2023,"date_issued":"2023-04-13","date_published":"2023-04-13","updated_at":"2026-07-27T20:18:56Z","subjects":["linoleic acid","T cell","CAR-T","adoptive cell therapy","metabolism","metabolic reprogramming","Settore MED/04 - Patologia Generale"],"languages":["eng"],"rights":["info:eu-repo/semantics/openAccess"],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["http://dx.doi.org/10.13130/nava-lauson-carina-b-_phd2023-04-13","10.13130/nava-lauson-carina-b-_phd2023-04-13"],"render_values":[{"text":"http://dx.doi.org/10.13130/nava-lauson-carina-b-_phd2023-04-13","href":"http://dx.doi.org/10.13130/nava-lauson-carina-b-_phd2023-04-13","code":true},{"text":"10.13130/nava-lauson-carina-b-_phd2023-04-13","href":"https://doi.org/10.13130/nava-lauson-carina-b-_phd2023-04-13","code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2434/958937","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["tutor: T. Manzo ; co-tutor: S. Santaguida ; phd coordinator: S. Minucci ; curators: B. Amati","C. Vernieri","D. Cantrell","P. Ho","C.B. NAVA LAUSON","MINUCCI, SAVERIO"]},{"key":"dc:creator","label":"Author","values":["NAVA LAUSON, CARINA B."]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2023-04-13"]},{"key":"dc:publisher","label":"Institution","values":["Università degli Studi di Milano"]},{"key":"dc:type","label":"Dc Type","values":["info:eu-repo/semantics/doctoralThesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["linoleic acid","T cell","CAR-T","adoptive cell therapy","metabolism","metabolic reprogramming","Settore MED/04 - Patologia Generale"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["info:eu-repo/semantics/openAccess"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2434/958937","http://dx.doi.org/10.13130/nava-lauson-carina-b-_phd2023-04-13","10.13130/nava-lauson-carina-b-_phd2023-04-13"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["T cell therapy (ACT) has achieved unprecedented clinical results in the treatment of cancer, but scarce intra-tumor infiltration, persistence and function of adoptively transferred T cells limit its efficacy, especially in solid tumors. Metabolic constraints imposed by the tumor microenvironment (TME) greatly influence the success of immune-based therapies. A common metabolic alteration in the TME is lipid accumulation, a feature often associated with defective anti-tumor responses. However, whether all lipids are detrimental to T cell functions and how they regulate different fate decisions remains poorly understood. Here, we identified Linoleic Acid (LA) as a major positive regulator of CTL activity. LA endows CTL with improved metabolic fitness and redirects them away from exhaustion and towards a memory-like phenotype with superior effector functions. Mechanistically, LA treatment fosters the formation of ER-mitochondria contacts (MERC) and mitochondrial-associated-membranes (MAMs), which in turn promotes calcium (Ca2+) signaling, mitochondrial energetics, and CTL effector functions. As a result, LA-instructed CD8+ T cells mediate superior control towards different tumor types both in vitro and in vivo following ACT on mouse models, overcoming the hustle of a highly immunosuppressive TME. Our results pave the way for a new generation of adoptive T cell-based therapies, where LA can be used during ex vivo CAR- and TCR- T cell manufacturing as a novel approach to achieve metabolic reprogramming and long-term functionality, broadening the therapeutic efficacy of ACT to a wide range of malignancies."]},{"key":"dc:title","label":"Title","values":["LINOLEIC ACID UNLEASHES THE ANTI-TUMOR POTENTIAL OF CD8 T CELLS BY PROMOTING METABOLIC REPROGRAMMING"]}]}],"canonical_facts":{"dc:contributor":["tutor: T. Manzo ; co-tutor: S. Santaguida ; phd coordinator: S. Minucci ; curators: B. Amati","C. Vernieri","D. Cantrell","P. Ho","C.B. NAVA LAUSON","MINUCCI, SAVERIO"],"dc:creator":["NAVA LAUSON, CARINA B."],"dc:date":["2023-04-13"],"dc:description":["T cell therapy (ACT) has achieved unprecedented clinical results in the treatment of cancer, but scarce intra-tumor infiltration, persistence and function of adoptively transferred T cells limit its efficacy, especially in solid tumors. Metabolic constraints imposed by the tumor microenvironment (TME) greatly influence the success of immune-based therapies. A common metabolic alteration in the TME is lipid accumulation, a feature often associated with defective anti-tumor responses. However, whether all lipids are detrimental to T cell functions and how they regulate different fate decisions remains poorly understood. Here, we identified Linoleic Acid (LA) as a major positive regulator of CTL activity. LA endows CTL with improved metabolic fitness and redirects them away from exhaustion and towards a memory-like phenotype with superior effector functions. Mechanistically, LA treatment fosters the formation of ER-mitochondria contacts (MERC) and mitochondrial-associated-membranes (MAMs), which in turn promotes calcium (Ca2+) signaling, mitochondrial energetics, and CTL effector functions. As a result, LA-instructed CD8+ T cells mediate superior control towards different tumor types both in vitro and in vivo following ACT on mouse models, overcoming the hustle of a highly immunosuppressive TME. Our results pave the way for a new generation of adoptive T cell-based therapies, where LA can be used during ex vivo CAR- and TCR- T cell manufacturing as a novel approach to achieve metabolic reprogramming and long-term functionality, broadening the therapeutic efficacy of ACT to a wide range of malignancies."],"dc:identifier":["https://hdl.handle.net/2434/958937","http://dx.doi.org/10.13130/nava-lauson-carina-b-_phd2023-04-13","10.13130/nava-lauson-carina-b-_phd2023-04-13"],"dc:language":["eng"],"dc:publisher":["Università degli Studi di Milano"],"dc:rights":["info:eu-repo/semantics/openAccess"],"dc:subject":["linoleic acid","T cell","CAR-T","adoptive cell therapy","metabolism","metabolic reprogramming","Settore MED/04 - Patologia Generale"],"dc:title":["LINOLEIC ACID UNLEASHES THE ANTI-TUMOR POTENTIAL OF CD8 T CELLS BY PROMOTING METABOLIC REPROGRAMMING"],"dc:type":["info:eu-repo/semantics/doctoralThesis"]},"updated_at":"2026-07-27T20:18:56Z"}