Modulação do sistema imunitário adaptativo na sequência adenoma-carcinoma num contexto de tumores colo-retais

O sistema imunitário tem um papel fundamental na iniciação e progressão do tumor. A interação entre tumores, quer hereditários quer esporádicos, e o sistema imunitário pode variar ao longo da progressão tumoral. Neste artigo fez-se uma análise das células imunitárias no microambiente tumoral, tal como de marcadores importantes para o sistema imunológico em displasias de baixo grau, alto grau e adenocarcinomas colo-retais.

Este estudo sugere que ao longo da progressão tumoral em ambos os contextos de cancros colo-retais, o microambiente torna-se mais propício para a imunotolerância. Este fenómeno decorre da diminuição do infiltrado imunitário ao invés da diminuição da imunogenicidade e da imunossupressão tumoral.

Autores e Afiliações:

João Augusto Freitas ^1,2,† , Irene Gullo ^1,2,3,4,† , Diogo Garcia ⁴, Sara Miranda ^1,2, Louisa Spaans ⁵,

Lídia Pinho ^1,2, Joana Reis ^1,2, Fabiana Sousa ⁶, Manuela Baptista ⁶, Carlos Resende ^1,2, Dina Leitão ⁴,

Cecília Durães ^1,2, José Luis Costa ^1,2, Fátima Carneiro ^1,2,3,4 and José Carlos Machado ^1,2,4

¹ Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, 4200-135 Porto, Portugal;

² Institute of Molecular Pathology and Immunology, University of Porto (Ipatimup), 4200-135 Porto, Portugal

³ Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ), 4200-319 Porto, Portugal

⁴ Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal;

⁵ Faculty of Health, Medicine and Life Sciences-Maastricht University, 6229 ER Maastricht, The Netherlands;

⁶ High Risk Consultation of Digestive Tumors, Department of General Surgery, Centro Hospitalar Universitário de São João (CHUSJ), 4200-319 Porto, Portugal; 

† Joint first authors.

Abstract:

Background. The tumor immune microenvironment exerts a pivotal influence in tumor initiation and progression. The aim of this study was to analyze the immune context of sporadic and familial adenomatous polyposis (FAP) lesions along the colorectal adenoma–carcinoma sequence (ACS). Methods. We analyzed immune cell counts (CD3+, CD4+, CD8+, Foxp3+, and CD57+), tumor mutation burden (TMB), MHC-I expression and PD-L1 expression of 59 FAP and 74 sporadic colorectal lesions, encompassing adenomas with low-grade dysplasia (LGD) (30 FAP; 30 sporadic),  adenomas with high-grade dysplasia (22 FAP; 30 sporadic), and invasive adenocarcinomas (7 FAP; 14 sporadic). Results. The sporadic colorectal ACS was characterized by (1) a stepwise decrease in immune cell counts, (2) an increase in TMB and MHC-I expression, and (3) a lower PD-L1 expression. In FAP lesions, we observed the same patterns, except for an increase in TMB along the ACS. FAP LGD lesions harbored lower Foxp3+ T cell counts than sporadic LGD lesions. A decrease in PD-L1 expression occurred earlier in FAP lesions compared to sporadic ones. Conclusions. The colorectal ACS is characterized by a progressive loss of adaptive immune infiltrate and by the  establishment of a progressively immune cold microenvironment. These changes do not appear to be related with the loss of immunogenicity of tumor cells, or to the onset of an immunosuppressive tumor microenvironment.

Revista: International Journal of Molecular Sciences

Link: https://doi.org/10.3390/ijms22189791