Deepak Gupta
Boris Chichkov
Zoltan Janos Vereb
Ibrahim T. Ozbolat- 1The Huck Institutes of the Life Sciences, Penn State University, University Park, PA, United States
- 2Engineering Science and Mechanics Department, Penn State University, University Park, PA, United States
- 3Cluster of Excellence PhoenixD, Leibniz University Hannover, Hannover, Germany
- 4Institute of Quantum Optics, Leibniz University Hannover, Hannover, Germany
- 5Regenerative Medicine and Cellular Pharmacology Research Laboratory, Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
- 6Research Institute of Translational Biomedicine, Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
- 7Department of Biomedical Engineering, Penn State University, University Park, PA, United States
- 8Materials Research Institute, Penn State University, University Park, PA, United States
- 9Department of Neurosurgery, Penn State University, Hershey, PA, United States
- 10Penn State Cancer Institute, Penn State University, Hershey, PA, United States
- 11Department of Medical Oncology, Cukurova University, Adana, Türkiye
Editorial on the Research Topic
Innovative 3D technologies in cancer immunity research and therapy
Cancer still lies outside our box of understanding. The conventional methods to dissect, assemble, and replicate a human tumor artificially need to be revamped. Innovative 3D technologies offer promising potential and pave the way to develop advanced engineering methods to fight against cancer.
For decades, cancer has been a major cause of death with nearly 20 million new cases reported worldwide with a high mortality of 10 million in 2020 (1). Scientists are striving hard to understand the mechanism behind the complex interplay between cancer cells and the immune system. Still, we are far from answering the fundamental question of how cancer cells evade the immune attack (2). Current understanding states that both innate and adaptive immune cells infiltrate the tumor and influence the cancer progression through their complex network of crosstalk with heterogeneous cellular and acellular components of the tumor microenvironment. Although conventional experimental models, such as in-vitro 2D or in-vivo animal models, have laid the foundation of our understanding of cancer-immune cell interactions, such model systems fail to recapitulate the interaction of human immune system within a tumor microenvironment, and their systemic effects (3). With technological advances, the development of advanced 3D engineered models, such as organoid systems coupled with 3D bioprinting, and interconnected body-on-a-chip microfluidic devices, have shown an impressive potential to mimic natural 3D tumor-immune-microenvironment to a great extent; thus, overcoming the limitations of the conventional methods.
The Research Topic Innovative 3D Technologies in Cancer Immunity Research and Therapy at Frontiers in Immunology is dedicated to this emerging field of research. Visalakshan et al. reviewed the state-of-the-art 3D modeling approaches such as engineered organoids, 3D bioprinted systems, organ-on-a-chip, and microfluidic models for T cell infiltration, cancer resistance, and immune suppression to advance our understanding of tumor immunology thus moving a step closer towards comprehending the intricate inter-connections of the tumor-immune-microenvironment. Miebach et al.‘s review in this Research Topic targets the scope and limitations of the chicken embryo model in cancer immunological research as an alternative to time-consuming and costly mammalian tumor models. The in-ovo models are naturally immunodeficient, vascularized with capillaries and post-capillary venules, and possess chorioallantoic membrane accessible for experimentation. It offers a more functional natural 3D model to comprehensively study the series of events in a metastatic cascade (4, 5), tumor-immune interaction, and establish a better prognosis of cancer while circumventing the tedious process of administrative ethical approvals.
Tumor stromal cells and cancer-associated fibroblasts (CAFs) play a crucial role in tumor progression, metastasis, and therapy resistance. Still, their interaction mechanism with tumor cells remains an uncompleted puzzle. Thus, co-culturing of these heterogeneous cells and organoids offers great potential to reveal the underlying mechanisms of tumor and immune cells interactions. Yuan et al.‘s review in this Research Topic discusses recent advances, applications, and prospects of co-culture model systems designed for cancer organoids coupled with immune cells, CAR-T cells, and CAFs. There are two preeminent research articles in this Research Topic demonstrating the development of 3D engineered co-culture systems to recapitulate the tumor-immune-microenvironment. Li et al. demonstrated a 3D bioprinted model that deposits cholangiocarcinoma (CCA) surrounded by stromal cells and observed their interaction for CCA proliferation, metastasis, and drug resistance. Strating et al. developed a co-culture system for colon cancer spheroids and CAFs to study their interplay and re-organization and analyzed their effects on ECM properties and T cell proliferation. Further, to obtain an integrative picture to better understand these heterogeneous cellular interactions visually, this Research Topic contains a method article, where Elaldi et al. reported the development of a 39-antibody panel integrated with Imaging mass cytometry technology with 13 new markers to target tumor cells, immune cells, T and B lymphocytes, CAFs, ECM protein, blood and lymphatic vessels and nerve fibers.
3D Engineered systems thus provide a promising scenario in the field of cancer immunology with researchers developing new multi-functional devices to understand tumor-immune-microenvironment and to mitigate the dependence on in-vivo models. Nevertheless, there are several challenges yet to be addressed. The current in-vitro models cannot replicate the high density of natural tumors, thus making it challenging to clinically translate the therapeutic agent, engineered in a lab, to penetrate a natural tumor effectively. Further, there is ample scope to engineer the multitude of functionalities in current 3D systems to reflect the complex interactions of immune cells with other heterogeneous cellular and acellular components in tumor-immune microenvironment (6). Despite these challenges, 3D technologies offer a plethora of potential and a reliable platform for cancer immunotherapy research to accelerate drug discovery, create personalized therapies and predict clinical outcomes while gradually replacing animal testing and avoiding ethical concerns.
Author contributions
DG drafted the editorial, and all co-editors contributed to the writing and revision of the article. All authors contributed to the article and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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References
1. Ferlay J, et al. Global cancer observatory: cancer today (2020). Lyon: International Agency for Research on Cancer. Available at: https://gco.iarc.fr/today (Accessed February 2021).
2. Gonzalez H, Hagerling C, Werb Z. Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes Dev (2018) 32(19-20):1267–84. doi: 10.1101/gad.314617.118
3. Dey M, Kim MH, Nagamine M, Karhan E, Kozhaya L, Dogan M, et al. Biofabrication of 3D breast cancer models for dissecting the cytotoxic response of human T cells expressing engineered MAIT cell receptors. Biofabrication (2022) 14(4):044105. doi: 10.1088/1758-5090/ac925a
4. Leong HS, Robertson AE, Stoletov K, Leith SJ, Chin CA, Chien AE, et al. Invadopodia are required for cancer cell extravasation and are a therapeutic target for metastasis. Cell Rep (2014) 8(5):1558–70. doi: 10.1016/j.celrep.2014.07.050
5. Zijlstra A, Lewis J, DeGryse B, Stuhlmann H, Quigley JP. The inhibition of tumor cell intravasation and subsequent metastasis via regulation of in vivo tumor cell motility by the tetraspanin CD151. Cancer Cell (2008) 13(3):221–34. doi: 10.1016/j.ccr.2008.01.031
Keywords: tumor models, cancer, bioprinting, cancer immune cell therapy, 3D technologies
Citation: Gupta D, Chichkov B, Vereb ZJ and Ozbolat IT (2023) Editorial: Innovative 3D technologies in cancer immunity research and therapy. Front. Immunol. 14:1235483. doi: 10.3389/fimmu.2023.1235483
Received: 06 June 2023; Accepted: 14 June 2023;
Published: 20 June 2023.
Edited and Reviewed by:
Katy Rezvani, University of Texas MD Anderson Cancer Center, United StatesCopyright © 2023 Gupta, Chichkov, Vereb and Ozbolat. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ibrahim T. Ozbolat, ito1@psu.edu