From Cancer to Immune Organoids: Innovative Preclinical Models to Dissect the Crosstalk between Cancer Cells and the Tumor Microenvironment

Abstract

Genomic-oriented oncology has improved tumor classification, treatment options, and patient outcomes. However, genetic heterogeneity, tumor cell plasticity, and the ability of cancer cells to hijack the tumor microenvironment (TME) represent a major roadblock for cancer eradication. Recent biotechnological advances in organotypic cell cultures have revolutionized biomedical research, opening new avenues to explore the use of cancer organoids in functional precision oncology, especially when genomics alone is not a determinant. Here, we outline the potential and the limitations of tumor organoids in preclinical and translational studies with a particular focus on lung cancer pathogenesis, highlighting their relevance in predicting therapy response, evaluating treatment toxicity, and designing novel anticancer strategies. Furthermore, we describe innovative organotypic coculture systems to dissect the crosstalk with the TME and to test the efficacy of different immunotherapy approaches, including adoptive cell therapy. Finally, we discuss the potential clinical relevance of microfluidic mini-organ technology, capable of reproducing tumor vasculature and the dynamics of tumor initiation and progression, as well as immunomodulatory interactions among tumor organoids, cancer-associated fibroblasts (CAFs) and immune cells, paving the way for next-generation immune precision oncology.

Keywords: immune organoids; organotypic cultures; patient-derived tumor organoids (PDTOs); patient-derived tumor xenografts (PDTXs); precision oncology; tumor microenvironment.

Figure 1

Advances and challenges in precision oncology. The implementation of next-generation sequencing with immunohistochemical analysis in the current decision-making process has improved patient stratification and outcomes, especially with the introduction of molecular targeted therapies in clinical practice. Emerging evidence highlights that therapy resistance is not only driven by genetics, but it also relies on cancer cell plasticity and on how cancer shapes the tumor microenvironment (TME). Therefore, innovative strategies are required for cancer eradication in a personalized manner. Created with BioRender.com.

Figure 2

Advantages of patient-derived tumor organoids in a co-clinical setting. During the conventional clinical workflow, patient-derived tumor organoids (PDTOs) can be established from both surgical resections and core biopsies. PDTOs can be generated using both air-liquid interphase and submerged cell culture conditions. After histological and molecular validation, PTDOs might be used in a co-clinical setting to explore different therapeutic strategies, identifying the best treatment for each patient in both in vitro and in vivo scenarios. Moreover, genetically modified PDTOs can be used to identify the molecular circuits involved in drug resistance and consequently to design innovative strategies to overcome drug resistance in a personalized manner. Created with BioRender.com.

Figure 3

Patient-derived tumor organoids for next-generation functional precision immuno-oncology. (a) Starting from small tumor fragments and using specific cell culture conditions, it is possible to preserve in vitro different populations of the tumor microenvironment (TME), including immune cells, for short-term studies. Alternatively, using innovative bioengineered devices, an ex vivo reconstitution of PDTOs with specific subpopulations of the TME is also possible, including natural killer (NK) cells, B-cells, T-cells, monocytes, cancer-associated fibroblasts (CAFs), and endothelial cells, including the tumor vasculature. Both technologies are suitable to explore innovative immune therapy approaches in a personalized manner. (b) Recent advances in the bio-fabrication of microfluidic devices resulted in the generation of a functional “mini-colon” to recapitulate normal colon morphogenesis and to dynamically track, with unprecedented resolution, colorectal cancer (CRC) initiation and progression. The mini-organ technology represents the most-advanced pipeline for the implementation of PDTOs in a co-clinical setting for the design of more effective individualized therapeutic strategies. Created with BioRender.com.