258MO - Discovery of synergistic effect for triple-negative breast cancer immunotherapy using tumor-microenvironment-on-chip

Background

Immune checkpoint inhibitors (ICI), such as anti-PD-1, are used to facilitate anti-cancer function of effector T cells, which gives a passable treatment effect to patients, and CD8⁺ T cell exhaustion is a key impediment to ICI treatment. To improve anti-cancer effect of ICI, combination therapy is a potential strategy. Chemo-immunotherapy combination augments therapeutic efficacy of ICI, but elevated adverse effects are accompanied with patients. Thus, a tumor-microenvironment-on-chip (TMoC) system was developed to identify synergism with ICI therapy to maximize treatment efficacies while reducing the side effects.

Methods

To accurately imitate in vivo drug response, the tumor environment needs to be effectively preserved in vitro. Oxygen gradient is a critical mechanism that leads to cellular heterogeneity, resulting in T cell exhaustion and immunotherapy failure. Herein, to study the interaction between drugs and tumor-microenvironment, TMoC was designed with characteristics of molecular gradients, including oxygen, nutrients, and drugs. Besides, CD8⁺ T cells exhibited diverse behavior in different areas in TMoC, which was highly similar to in vivo conditions. Further, the efficacy of CD8⁺ T cells against tumors could also be quantified to assess the synergism of immune-chemotherapy combinations.

Results

TMoC had been shown to have an oxygen gradient. In the region of relative hypoxia, exhaustion of CD8⁺ T cells, anti-apoptosis of cancer cells, and drug resistance genes were significantly up-regulated. To improve the effects of anti-PD-1, we introduced several potential chemotherapy agents. A TGF-β1 receptor antagonist, and a MAPK pathway inhibitor were identified to synergize with anti-PD-1 in hypoxia or normoxia, respectively. Further, the drug evaluation in TMoC was confirmed to be the same in orthotopic preclinical cancer model.

Conclusions

Characteristics of in vivo tumor environment were perfectly preserved in TMoC, and responses to the drug combinations were highly similar. Thus, we concluded that TMoC could serve as a powerful tool to improve drug development, and clinical diagnosis purposes.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Ministry of Science and Technology, R.O.C.

Disclosure

All authors have declared no conflicts of interest.