Investigadores do i3S desenvolvem nova estratégia para criar uma super célula CAR-T contra os tumores sólidos

Uma equipa do Instituto de Investigação e Inovação em Saúde da Universidade do Porto (i3S), liderada por Salomé Pinho, descobriu uma nova estratégia de tornar as terapias com células T (CAR-T) mais eficazes contra tumores sólidos. Os resultados foram publicados na revista Cancer Immunology Research, da American Association for Cancer Research(AACR).

Os investigadores mostraram que, no cancro colorretal, os linfócitos T infiltrados no tumor sofrem alterações significativas nos açúcares expressos à superfície (glicanos), reduzindo a sua capacidade de combater a doença. Através da edição genética com a tecnologia CRISPR/Cas9, eliminaram o gene MGAT5, responsável pela produção desses glicanos prejudiciais, conseguindo restaurar a função das células T, tornando-as menos exaustas, mais resistentes e eficazes a combater de células tumorais.

Aplicando esta estratégia à terapia CAR-T, já utilizada em cancros hematológicos, mas com eficácia limitada em tumores sólidos, a equipa desenvolveu as chamadas células “Glyco-CAR-T”. Estas células super CAR-T glico-modificadas revelaram uma capacidade citotóxica superior e uma maior habilidade em controlar o crescimento de tumores sólidos em modelos experimentais in vivo.

O estudo foi liderado por Catarina Azevedo, primeira autora, com o apoio de bolsas da FCT, FLAD e Fulbright, em colaboração com Ângela Fernandes (i3S) e Greg Delgoffe (Universidade de Pittsburgh).

Autores e Afiliações: 

Catarina M. Azevedo^1,2, Bingxian Xie^3,4, William G. Gunn^3,4, Ronal M. Peralta^3,4, Carolina S. Dantas^1,2, Henrique Fernandes-Mendes^2,9, Supriya Joshi^3,4, Victoria Dean^3,4, Pedro Almeida¹, Drew Wilfahrt^3,4, Nuno Mendes¹, Julian López Portero^5,6,7, Carmen Poves^7,8, María Jesús Fernández-Aceñero^5,6, Ricardo Marcos-Pinto^2,9, Ângela Fernandes¹*, Greg M. Delgoffe^3,4*, Salomé S. Pinho^1,2,10,11*

¹i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal

²ICBAS – School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal

³Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

⁴Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA

⁵Department of Legal medicine, Psychiatry and Surgical Pathology, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain

⁶Department of Surgical Pathology, Hospital Clínico San Carlos, Madrid, Spain

⁷Instituto de Investigación del Hospital Clínico San Carlos (IdISSC), Madrid, Spain

⁸Gastroenterology Department, Endoscopy Unit Hospital Clínico San Carlos, Madrid, Spain

⁹Department of Gastroenterology, Santo António University Hospital Center, Porto, Portugal

¹⁰Faculty of Medicine, University of Porto, Porto, Portugal

*These authors contributed equally/Senior authors

¹¹Lead contact

Abstract:

T-cell therapies have transformed cancer treatment. While surface glycans have been shown to play critical roles in regulating T-cell development and function, whether and how the glycome influences T cell–mediated tumor immunity remains an area of active investigation. In this study, we show that the intratumoral T-cell glycome is altered early in human colorectal cancer, with substantial changes in branched N-glycans. We demonstrated that CD8⁺ T cells expressing β1,6-GlcNAc branched N-glycans adopted an exhausted phenotype, marked by increased PD1 and Tim3 expression. CRISPR/Cas9 deletion of key branching glycosyltransferase genes revealed that Mgat5 played a prominent role in T-cell exhaustion. In culture-based assays and tumor studies, Mgat5 deletion in CD8⁺ T cells resulted in improved cancer cell killing. These findings prompted assessment of whether MGAT5 deletion in anti-CD19 chimeric-antigen receptor (CAR) T cells could enable this therapeutic modality in a solid tumor setting. We showed that MGAT5 KO anti-CD19-CAR T cells inhibited the growth of CD19-transduced tumors. Together, these findings show that MGAT5-mediated branched N-glycans regulate CD8⁺ T-cell function in cancer and provide a strategy to enhance antitumor activity of native and CAR T cells.

Revista: Cancer Immunology Research journal

Link: https://doi.org/10.1158/2326-6066.CIR-25-0313