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Precision nanotechnology-based therapeutic approaches to enhance tumor-immune cells crosstalk within melanoma stromal microenvironment

2023-09Tese de doutoramento Acesso restrito
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datacite.subject.fosCiências Médicas::Medicina Básicapt_PT
dc.contributor.advisorFerreira, Helena Isabel Fialho Florindo Roque
dc.contributor.advisorSatchi-Fainaro, Ronit
dc.contributor.authorCarreira, Barbara
dc.date.accessioned2024-06-03T09:08:10Z
dc.date.available2024-06-03T09:08:10Z
dc.date.issued2023-09
dc.date.submitted2023-03
dc.description.abstractDespite the remarkable efficiency of immune checkpoint modulators against metastatic melanoma, only a small percentage of patients respond to these therapies. Among the responders, clinical trials report immune-mediated side effects and disease relapse. Immune checkpoint inhibitors inefficiency is being attributed to tumor-related immunosuppression pathways and limited infiltration of effector T cells. To overcome these limitations, new synergistic strategies are urgently needed. To that end, we focused on the development of a precision nanosystem based therapy to specifically target dendritic cells (DC) and successfully modulate melanoma-immune cell interactions by expanding the range of targeted cells in a site-specific manner. For this purpose, we designed, synthesized, and characterized poly(lactic acid) and poly(lactic-co-glycol) (PLA/PLGA)-based nano-vaccines using mannose-grafted polymers to deliver combinations of melanoma neoantigen, toll-like receptor ligands, and regulators of the PD-1/PD-L1 pathway. These cancer nano-vaccinesamplified antitumor immune responses by increasing tumor-associated antigen recognition, processing, and presentation to effector T cells. The polymeric nanoparticles presented spherical shape with an average diameter of 180 nm, displaying a narrow polydispersity index, near-neutral surface charge, and high loadings of the immune regulators. Both subcutaneous and intranasal immunizations induced the activation and maturation of DC within draining lymph nodes and triggered the systemic activation of neoantigen-specific cytotoxic T cells. Treatment with the combination of the therapeutic nano-vaccineswith PD-1/PD-L1 modulators in vivo led to increased tumor inhibition in orthotopic primary melanoma-bearing mice, with minimal systemic toxicity. The combination of the nano-vaccine with the PD-L1 monoclonal antibody was the most effective, with maximal tumor growth inhibition, translated into extensive infiltration of cytotoxic CD8+ T cells into the tumor microenvironment and reduced expression of immunosuppressor cells. At the metastatic disease, followed by primary tumor resection, the intranasal immunization of the therapeutic nano-vaccine combined with the PD-L1 immune checkpoint inhibitor led to the prevention of melanoma brain metastases. The combination strategy led to 100% survival at 52 days followed intracranial tumor inoculation and recapitulation into a T-cell inflamed brain tumor microenvironment. Altogether, the synergy between the nano-vaccine and the PD-L1 antibody provides essential insights to devise alternative combination regimens to improve the efficacy of immune checkpoint inhibitors in metastatic melanoma, thus opening a new line for polymeric nano-vaccines as a potential tool to advance clinical response to advanced melanoma.pt_PT
dc.description.provenanceSubmitted by Paula Guerreiro (passarinho@reitoria.ulisboa.pt) on 2024-05-24T11:34:35Z No. of bitstreams: 1 scnd990026354741662_td_Ana_Carreira.pdf: 2419655 bytes, checksum: 4e22078bb7d9fab944a120221c1ad97d (MD5)en
dc.description.provenanceMade available in DSpace on 2024-06-03T09:08:10Z (GMT). No. of bitstreams: 1 scnd990026354741662_td_Ana_Carreira.pdf: 2419655 bytes, checksum: 4e22078bb7d9fab944a120221c1ad97d (MD5) Previous issue date: 2023-09en
dc.description.sponsorship”la Caixa” Foundationpt_PT
dc.identifier.tid101675941pt_PT
dc.identifier.urihttp://hdl.handle.net/10451/64956
dc.language.isoengpt_PT
dc.relationPrecision nanotechnology-based therapeutic approaches to enhance tumor-immune cells crosstalk within melanoma stromal microenvironment
dc.relationMultifunctional nano-immunotherapy for melanoma brain metastases treatment
dc.relationNew opportunities for small molecules in immuno-oncology
dc.relationResearch Institute for Medicines
dc.relationResearch Institute for Medicines
dc.subjectNanovacinaspt_PT
dc.subjectimunoterapiapt_PT
dc.subjectintranasalpt_PT
dc.subjectPD-L1pt_PT
dc.subjectmetástases cerebrais de melanomapt_PT
dc.subjectnano-vaccinespt_PT
dc.subjectimmunotherapypt_PT
dc.subjectintranasalpt_PT
dc.subjectmelanoma brain metástasespt_PT
dc.titlePrecision nanotechnology-based therapeutic approaches to enhance tumor-immune cells crosstalk within melanoma stromal microenvironmentpt_PT
dc.typedoctoral thesis
dspace.entity.typePublication
oaire.awardTitlePrecision nanotechnology-based therapeutic approaches to enhance tumor-immune cells crosstalk within melanoma stromal microenvironment
oaire.awardTitleMultifunctional nano-immunotherapy for melanoma brain metastases treatment
oaire.awardTitleNew opportunities for small molecules in immuno-oncology
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleResearch Institute for Medicines
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F131969%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/Concurso Transnacional Conjunto da ERA-NET EuroNanoMed II - 2016/ENMed%2F0051%2F2016/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBTM-SAL%2F4350%2F2021/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/EXPL%2FMED-QUI%2F1316%2F2021/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/UTAP-EXPL%2FNPN%2F0041%2F2021/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04138%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04138%2F2020/PT
oaire.fundingStreamConcurso Transnacional Conjunto da ERA-NET EuroNanoMed II - 2016
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
person.familyNameCarreira
person.givenNameBárbara
person.identifier.ciencia-idC017-F1FA-FB56
person.identifier.orcid0000-0001-6382-5745
person.identifier.scopus-author-id57195721985
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.contributor.authoremailrepositorio@reitoria.ulisboa.pt
rcaap.rightsrestrictedAccesspt_PT
rcaap.typedoctoralThesispt_PT
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thesis.degree.nameTese de doutoramento, Farmácia (Tecnologia Farmacêutica), Universidade de Lisboa, Faculdade de Farmácia, 2023pt_PT

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