3D models in the new era of immune oncology: focus on T cells, CAF and ECM

Abstract

Immune checkpoint inhibitor therapy has changed clinical practice for patients with different cancers, since these agents have demonstrated a significant improvement of overall survival and are effective in many patients. However, an intrinsic or acquired resistance frequently occur and biomarkers predictive of responsiveness should help in patient selection and in defining the adequate treatment options. A deep analysis of the complexity of the tumor microenvironment is likely to further advance the field and hopefully identify more effective combined immunotherapeutic strategies. Here we review the current knowledge on tumor microenvironment, focusing on T cells, cancer associated fibroblasts and extracellular matrix. The use of 3D cell culture models to resemble tumor microenvironment landscape and to screen immunomodulatory drugs is also reviewed.

Keywords: 3D culture models; Cancer associated fibroblasts; Extracellular matrix; Immune oncology; T cells; Tumor microenvironment.

Fig. 1

Modelling the TME. Schematic representation of the major preclinical models and bio-fabrication techniques (a-g) employed to recapitulate TME complexity. For each model advantages (blue) and limitations (beige) are reported

Fig. 2

Schema of the methods to measure the cellular biomechanics properties. Standard methods, such as AFM (a), micropillar deformation (b), magnetic twisting cytometry (c), optical tweezers (d), micropipette aspiration (e), deformability cytometry (f) and OCE (g), require the application of contact forces to the extracellular matrix and measure stiffness from cellular displacement. The contact requirement makes these methods destructive and not capable to retrieve volumetric information. On the other hand, typical noncontact techniques, such as particle tracking (h), are either limited by an intrinsically low spatial resolution or require sample labelling through the use of nanoparticles. A promising method to non-invasively assess the extracellular and intracellular biomechanics in 3D is Brillouin microscopy (i), where light probes thermally activated spontaneous acoustic waves. Adapted by permission from Springer Nature: Bao G and Suresh S. Cell and molecular mechanics of biological materials. Nat Mater. 2003;2(11):715-25, © 2003 [158]