In Vitro Veritas: From 2D Cultures to Organ-on-a-Chip Models to Study Immunogenic Cell Death in the Tumor Microenvironment

Abstract

Immunogenic cell death (ICD) is a functionally unique form of cell death that promotes a T-cell-dependent anti-tumor immune response specific to antigens originating from dying cancer cells. Many anticancer agents and strategies induce ICD, but despite their robust effects in vitro and in vivo on mice, translation into the clinic remains challenging. A major hindrance in antitumor research is the poor predictive ability of classic 2D in vitro models, which do not consider tumor biological complexity, such as the contribution of the tumor microenvironment (TME), which plays a crucial role in immunosuppression and cancer evasion. In this review, we describe different tumor models, from 2D cultures to organ-on-a-chip technology, as well as spheroids and perfusion bioreactors, all of which mimic the different degrees of the TME complexity. Next, we discuss how 3D cell cultures can be applied to study ICD and how to increase the translational potential of the ICD inducers. Finally, novel research directions are provided regarding ICD in the 3D cellular context which may lead to novel immunotherapies for cancer.

Microbes mediated immunogenic cell death in cancer immunotherapy

“…To address these issues, organ‐on‐a‐chip models have gained much attention as a novel and promising experimental platform to investigate the interaction between tumor and immunity. This platform would benefit the elucidation of the molecular mechanisms and improve the success of translational studies of ICD inducers 133 . What's more, the combination strategy of ICD inducers and cancer regimens is a promising therapy, however, how to optimize the timing and dose of combination therapy remained to be solved.…”

“…Over 450 clinical trials have been conducted on the combination therapy between ICD inducers and anti-PD-1/ PD-L1 inhibitors according to the records in the Clini calTr ials.gov database. 132 133 What's more, the combination strategy of ICD inducers and cancer regimens is a promising therapy, however, how to optimize the timing and dose of combination therapy remained to be solved.…”

Out of Box Thinking to Tangible Science: A Benchmark History of 3D Bio-Printing in Regenerative Medicine and Tissues Engineering

“…Meanwhile, futuristic 3D-BP models can fabricate the native patient-derived tumors cells with the engineered T cells to test their efficacy in deteriorating the tumor [134]. However, it is certainly a challenging task to involve insights into the immunogenic mechanism of T cells in the tumor environment, which may lead to new experimental immunotherapies for cancer [135]. As a conclusive remark, integration of 3D-BP with allied technologies such as microarrays, AI, IoT based models, microfluidics and bioprinted organ/human-on-a-chip models would shorten the pipeline of pre-clinical drug testing trials and produce a viable choice of organ substitutes [136,137].…”

Trial watch: chemotherapy-induced immunogenic cell death in oncology

“…Over the years, at least two pre-clinical criteria have been established to classify an anti-cancer therapy as a potential ICD inducer 129 , 130 . First criterion is that a therapy should be able to induce tumor regression in an immuno-competent, but not immuno-deficient, mouse setting 131–133 . Secondly, the cancer cells treated with an ICD inducer should serve as an anti-cancer vaccine in a prophylactic setting 5 , 134–139 .…”