Publicaciones científicas

Short-term cultured tumor fragments to study immunotherapy combinations based on CD137 (4-1BB) agonism

09-jul-2024 | Revista: Oncoimmunology

Iñaki Eguren-Santamaría  1   2   3 , Inmaculada Rodríguez  1   3 , Claudia Herrero-Martin  1   3 , Eva Fernández de Piérola  1   3 , Arantza Azpilikueta  1   3 , Sandra Sánchez-Gregorio  1   3 , Elixabet Bolaños  1   3 , Gabriel Gomis  1   3 , Paula Molero-Glez  1   3 , Enrique Chacón  4 , José Ángel Mínguez  4 , Santiago Chiva  5 , Fernando Diez-Caballero  5 , Carlos de Andrea  3   6 , Álvaro Teijeira  1   3   7 , Miguel F Sanmamed  1   2   3   7 , Ignacio Melero  3   7   8   9


Abstract

Biomarkers for cancer immunotherapy are an unmet medical need. The group of Daniela Thommen at the NKI recently reported on novel methodologies based on short-term cultures of patient-derived tumor fragments whose cytokine concentrations in the supernatants and activation markers on infiltrating T cells were associated with clinical response to PD-1 blockade.

We set up a similar culture technology with tumor-derived fragments using mouse tumors transplanted into syngeneic immunocompetent mice to test an agonist anti-CD137 mAb and its combinations with anti-PD-1 and/or anti-TGF-β. Increases in IFNγ concentrations in the tissue culture supernatants were detected upon in-culture activation with the anti-CD137 and anti-PD-1 mAb combinations or concanavalin A as a positive control. No other cytokine from a wide array was informative of stimulation with these mAbs.

Interestingly, increases in Ki67 and other activation markers were substantiated in lymphocytes from cell suspensions gathered at the end of 72 h cultures. In mice bearing bilateral tumors in which one was excised prior to in vivo anti-CD137 + anti-PD-1 treatment to perform the fragment culture evaluation, no association was found between IFNγ production from the fragments and the in vivo therapeutic outcome in the non-resected contralateral tumors.

The experimental system permitted freezing and thawing of the fragments with similar functional outcomes. Using a series of patient-derived tumor fragments from excised solid malignancies, we showed IFNγ production in a fraction of the studied cases, that was conserved in frozen/thawed fragments. The small tumor fragment culture technique seems suitable to preclinically explore immunotherapy combinations.

CITA DEL ARTÍCULO  Oncoimmunology. 2024 Jul 9;13(1):2373519.  doi: 10.1080/2162402X.2024.2373519