Tissues and Tumor Microenvironment (TME) in 3D: Models to Shed Light on Immunosuppression in Cancer

Abstract

Immunosuppression in cancer has emerged as a major hurdle to immunotherapy efforts. Immunosuppression can arise from oncogene-induced signaling within the tumor as well as from tumor-associated immune cells. Understanding various mechanisms by which the tumor can undermine and evade therapy is critical in improving current cancer immunotherapies. While mouse models have allowed for the characterization of key immune cell types and their role in tumor development, extrapolating these mechanisms to patients has been challenging. There is need for better models to unravel the effects of genetic alterations inherent in tumor cells and immune cells isolated from tumors on tumor growth and to investigate the feasibility of immunotherapy. Three-dimensional (3D) organoid model systems have developed rapidly over the past few years and allow for incorporation of components of the tumor microenvironment such as immune cells and the stroma. This bears great promise for derivation of patient-specific models in a dish for understanding and determining the impact on personalized immunotherapy. In this review, we will highlight the significance of current experimental models employed in the study of tumor immunosuppression and evaluate current tumor organoid-immune cell co-culture systems and their potential impact in shedding light on cancer immunosuppression.

Lung Cancer Organoids: The Rough Path to Personalized Medicine

“…Therefore, dissecting tumor–TME interactions through suitable co-culture platforms is essential to understand the biological mechanisms underlying all the stages of tumor development. Creating faithful models of the normal and neoplastic lung microenvironment is particularly important for several reasons: first, to allow a better understanding of lung cancer initiation upon chronic inflammation caused by chemicals, smoking, or air pollution; second, to identify new therapeutic strategies that target the pro-tumor and pro-metastatic effects of the TME; third, to study cancer immunosuppression and increase the efficacy of immune-based therapies [ 73 ]; and finally, to understand the properties of the lung microenvironment as a metastatic niche, since the majority of solid tumors metastasize to the lungs [ 74 ]. To this end, a complex bronchioalveolar lung organoid (BALO) system has been recently developed by culturing mouse bronchioalveolar stem cells with lung-resident mesenchymal stem cells and macrophages, thus providing new opportunities to study epithelial–immune–mesenchymal interactions in a normal lung in vitro model [ 75 ].…”

Going with the Flow: Modeling the Tumor Microenvironment Using Microfluidic Technology

“…By integrating 3D culture systems and biomaterials, multiple 3D culture models, including spheroids, organoids, and 3D bioprinting, have been developed [ 81 , 96 , 97 ] and applied in various types of cancers, such as melanoma [ 59 , 98 ], breast [ 99 , 100 , 101 ], prostate [ 102 ], bladder [ 103 ], pancreas [ 104 ], and head and neck [ 105 ]. Multicellular tumor spheroids (MTSs) comprise multiple cancer cells that self-assemble into 3D spherical structures.…”

“…Depending on the cell sources they are created from, such as cell lines, multicellular mixtures, and patient-derived tissues, different models have been demonstrated [ 107 ]. Cancer cell line-derived MTSs are commonly used for convenience and ease of generation, as well as for variety of application, including drug screening and evaluation of drug penetrance [ 97 ]. As cancer cell line-derived MTSs lack immune cells, a variety of coculture systems have been developed (discussed further in Section 3.3.5 ).…”

Oncolytic adenovirus-mediated expression of decorin facilitates CAIX-targeting CAR-T therapy against renal cell carcinoma

“… 1 , 2 Recently many research papers support that the tumor microenvironment (TME) plays a critical role in tumor development and progression. 3 , 4 Various factors among TME can produce physical and immune barriers to the host immune system. Therefore, there is an urgent need to overcome these barriers to improve antitumor activity.…”