Immune organoids: from tumor modeling to precision oncology

Recent advances in the patient-derived tumor organoid (PDO) platform have allowed modeling of the in vivo immune tumor microenvironment. In assembloids, tumor-only PDOs are reconstituted with autologous immune cell components from various sources. Diverse culture methods have been developed to generate PDOs that retain native tumor-infiltrating immune cells. Ongoing efforts are correlating PDO immunological responses to immune checkpoint inhibitor treatment with patient clinical outcomes. Cancer immunotherapies, particularly immune checkpoint inhibitors, are rapidly becoming standard-of-care for many cancers. The ascendance of immune checkpoint inhibitor treatment and limitations in the accurate prediction of clinical response thereof have provided significant impetus to develop preclinical models that can guide therapeutic intervention. Traditional organoid culture methods that exclusively grow tumor epithelium as patient-derived organoids are under investigation as a personalized platform for drug discovery and for predicting clinical efficacy of chemotherapies and targeted agents. Recently, the patient-derived tumor organoid platform has evolved to contain more complex stromal and immune compartments needed to assess immunotherapeutic efficacy. We review the different methodologies for developing a more holistic patient-derived tumor organoid platform and for modeling the native immune tumor microenvironment. Cancer immunotherapies, particularly immune checkpoint inhibitors, are rapidly becoming standard-of-care for many cancers. The ascendance of immune checkpoint inhibitor treatment and limitations in the accurate prediction of clinical response thereof have provided significant impetus to develop preclinical models that can guide therapeutic intervention. Traditional organoid culture methods that exclusively grow tumor epithelium as patient-derived organoids are under investigation as a personalized platform for drug discovery and for predicting clinical efficacy of chemotherapies and targeted agents. Recently, the patient-derived tumor organoid platform has evolved to contain more complex stromal and immune compartments needed to assess immunotherapeutic efficacy. We review the different methodologies for developing a more holistic patient-derived tumor organoid platform and for modeling the native immune tumor microenvironment. ex vivo 3D culture platform whereby minced tissue fragments are embedded in a collagen extracellular matrix on top of a transwell insert that is exposed to air. is a murine melanoma cell line. formulations that mimic the extracellular matrix for cell culture purposes. is a murine colon carcinoma cell line. negative co-stimulatory molecule that downregulates T cell immune responses. increase in repeated DNA sequences that results from impaired DNA mismatch repair. type of immunotherapy that blocks negative regulators of the immune response, thereby increasing antitumor immunity. is a murine colon adenocarcinoma cell line. loss of function of one or more enzymes involved in the repair of nucleotide mismatch errors. enzymes involved in the repair of nucleotide mismatch errors are intact and functional. ex vivo 3D culture platform whereby dissociated murine tumor tissues are embedded in a collagen extracellular matrix and injected into a 3D microfluidic device. ex vivo 3D culture platform whereby dissociated human tumor tissues are embedded in a collagen extracellular matrix and injected into a 3D microfluidic device. ex vivo 3D culture platform whereby different areas of a human tumor are minced into 1–2 mm3 tumor fragments and individually embedded into a collagen-based extracellular matrix. ex vivo 3D culture platform whereby dissociated human tumor tissues are embedded into an extracellular matrix scaffold, allowing for retention of the phenotypic and genetic heterogeneity of the original tumor. in vivo preclinical model platform that involves the engraftment of primary clinical tumors into immunodeficient organisms, allowing for retention of the phenotypic and genetic heterogeneity of the original tumor. lymphocytes isolated from the peripheral blood. negative co-stimulatory molecule that downregulates T cell immune responses. expressed by antigen-presenting cells and tumor cells, and is the principal ligand for PD-1. methodology to measure tumor burden in evaluating the efficacy of cancer therapeutics. protein complex found on the surface of T cells that recognize peptide antigens bound to major histocompatibility complex molecules. lymphocytic cell populations that have invaded the tumor tissue, which can be isolated, expanded, and used as a type of immunotherapy. complex environment surrounding a tumor, including fibroblasts, blood vessels, infiltrating immune cells, and extracellular matrix. quantification of gene mutations that occur in the genome of a cancer cell.