| Texto completo | |
| Autor(es): |
Pivetta, Renata Schmieder
;
de Campos, Najla Santos Pacheco
;
Kinker, Gabriela Sarti
;
Beserra, Adriano de Oliveira
;
Marasco, Wayne Anthony
;
Medina, Tiago da Silva
;
dos Santos, Tiago Goss
;
Rodrigues, Tiago
;
Suarez, Eloah Rabello
Número total de Autores: 9
|
| Tipo de documento: | Artigo Científico |
| Fonte: | European Journal of Pharmaceutical Sciences; v. 213, p. 10-pg., 2025-08-06. |
| Resumo | |
The carbonic anhydrase IX (CAIX) expression occurs in most cases of clear cell renal cell carcinoma (ccRCC). This tumor type is characterized by an immunosuppressive microenvironment, where approximately one-fourth of patients overexpress the programmed cell death ligand-1 (PD-L1), significantly increasing their risk of death. Herein, we present a secondary effect of CAIX inhibition using monoclonal antibodies (mAbs) and CAR T cells, leading to PD-L1 downregulation in ccRCC and in vivo immune checkpoint blockade. We identified a positive correlation between CAIX and PD-L1 expression in ccRCC cell lines using in silico RNA-seq data analysis, prompting us to perform fluorescence-activated cell sorting of SKRC52 ccRCC cell subpopulations based on their positive or negative expression of CAIX and PD-L1. After two weeks in culture, the cell population selected to be negative for CAIX and positive for PD-L1 became negative for CAIX and PD-L1. To explore the phenomenon, CAIX blockade was performed using two anti-CAIX monoclonal antibodies (mAbs) in multiple doses in two CAIX+ PD-L1+ clear cell renal cell carcinoma (ccRCC) cell lines. The expression of CAIX and PD-L1 decreased after treatment with the mAbs, and the PI3K/Akt signaling pathway is involved in this modulation. CAIXtargeted CAR T cells in vivo also reduced PD-L1 expression, resulting in superior CD3 infiltration and granzyme B expression, which decreased T cell exhaustion. Our findings demonstrate that CAIX-targeted immunotherapies can induce an indirect immune checkpoint blockade by PD-L1 downregulation. (AU) | |
| Processo FAPESP: | 23/03631-3 - Potencializando a infiltração e funcionalidade de linfócitos T CAR em tumores sólidos por modulação de integrinas |
| Beneficiário: | Eloah Rabello Suarez |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |
| Processo FAPESP: | 18/17656-0 - Imunoterapia de nova geração - Direcionamento de linfócitos contendo receptores quiméricos para o combate ao câncer e bloqueio do checkpoint imunológico: eficácia terapêutica e estudos moleculares de mecanismos de exaustão de linfócitos. |
| Beneficiário: | Eloah Rabello Suarez |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |