Natural killer cells and immune-checkpoint inhibitor therapy: Current knowledge and new challenges

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Recent Advances of Organ-on-a-Chip in Cancer Modeling Research

Photodynamic therapy (PDT) is a promising non-invasive phototherapeutic approach for cancer therapy that can eliminate local tumor cells and produce systemic antitumor immune responses. In recent years, significant efforts have been made in developing strategies to further investigate the immune mechanisms triggered by PDT. The majority of in vitro experimental models still rely on the two-dimensional (2D) cell cultures that do not mimic a three-dimensional (3D) cellular environment in the human body, such as cellular heterogeneity, nutrient gradient, growth mechanisms, and the interaction between cells as well as the extracellular matrix (ECM) and therapeutic resistance to anticancer treatments. In addition, in vivo animal studies are highly expensive and time consuming, which may also show physiological discrepancies between animals and humans. In this sense, there is growing interest in the utilization of 3D tumor models, since they precisely mimic different features of solid tumors. This review summarizes the characteristics and techniques for 3D tumor model generation. Furthermore, we provide an overview of innate and adaptive immune responses induced by PDT in several in vitro and in vivo tumor models. Future perspectives are highlighted for further enhancing PDT immune responses as well as ideal experimental models for antitumor immune response studies.

Photodynamic Therapy-Mediated Immune Responses in Three-Dimensional Tumor Models

A major challenge in oncology drug development is to elucidate why drugs that show promising results in cancer cell lines in vitro fail in mouse studies or human trials. One of the fundamental steps toward solving this problem is to better predict how in vitro potency translates into in vivo efficacy. A common approach to infer whether a model will respond in vivo is based on in vitro half-maximal inhibitory concentration values (IC50 ), but yields limited quantitative comparison between cell lines and drugs, potentially because cell division and death rates differ between cell lines and in vivo models. Other methods based either on mechanistic modeling or machine learning require molecular insights or extensive training data, limiting their use for early drug development. To address these challenges, we propose a mathematical model integrating in vitro growth rate inhibition values with pharmacokinetic parameters to estimate in vivo drug response. Upon calibration with a drug-specific factor, our model yields precise estimates of tumor growth rate inhibition for in vivo studies based on in vitro data. We then demonstrate how our model can be used to study dosing schedules and perform sensitivity analyses. In addition, it provides meaningful metrics to assess association with genotypes and guide clinical trial design. By relying on commonly collected data, our approach shows great promise for optimizing drug development, better characterizing the efficacy of novel molecules targeting proliferation, and identifying more robust biomarkers of sensitivity while limiting the number of in vivo experiments. 

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/psp4.12836

Growth‐rate model predicts in vivo tumor response from in vitro data

Adoptive cell therapy in solid tumors, such as melanoma, is impaired, but little is known about the role that the fibroblasts present in the tumor microenvironment could exert. However, the mechanism at play is not well understood, partly due to the lack of relevant pre-clinical models. Three-dimensional culture and microfluidic chips are used to recapitulate the dynamic interactions among different types of cells in the tumor microenvironment in controlled and physiological settings. In this brief report, we propose a reductionist melanoma-on-a-chip model for evaluating the essential role of fibroblasts in the antitumor activity of lymphocytes. To this end, 3D melanoma spheroids were monocultured and co-cultured with human dermal fibroblasts and the NK-92 cell migration towards the tumor compartment was tested in a commercially available microfluidic device. Utilizing confocal microscopy, we observed the different recruitment of NK-92 cells in the presence and absence of fibroblasts. Our results show that fibroblasts’ presence inhibits immune effector recruiting by exploiting a 3D pre-clinical tumor model.

/pdf/fibroblasts-impair-migration-and-antitumor-activity-of-nk-92-2k08516b.pdf

Fibroblasts Impair Migration and Antitumor Activity of NK-92 Lymphocytes in a Melanoma-on-Chip Model

Several approaches have shown that the immune response against tumors strongly affects patients' clinical outcome. Thus, the study of anti-tumor immunity is critical to understand and potentiate the mechanisms underlying the elimination of tumor cells. Natural killer (NK) cells are members of innate immunity and represent powerful anti-tumor effectors, able to eliminate tumor cells without a previous sensitization. Thus, the study of their involvement in anti-tumor responses is critical for clinical translation. This analysis has been performed in vitro, co-incubating NK with tumor cells and quantifying the cytotoxic activity of NK cells. In vivo confirmation has been applied to overcome the limits of in vitro testing, however, the innate immunity of mice and humans is different, leading to discrepancies. Different activating receptors on NK cells and counter-ligands on tumor cells are involved in the antitumor response, and innate immunity is strictly dependent on the specific microenvironment where it takes place. Thus, three-dimensional (3D) culture systems, where NK and tumor cells can interact in a tissue-like architecture, have been created. For example, tumor cell spheroids and primary organoids derived from several tumor types, have been used so far to analyze innate immune response, replacing animal models. Herein, we briefly introduce NK cells and analyze and discuss in detail the properties of 3D tumor culture systems and their use for the study of tumor cell interactions with NK cells.

Jordi Leonardo Castrillo Fernadez

Papers

Three-Dimensional Culture Models to Study Innate Anti-Tumor Immune Response: Advantages and Disadvantages