Breast cancer on a chip

There are different mechanisms by which the body reacts to the introduction of extraneous agents. One of them is associated with T-cells of the immune system, on the surface of which there are checkpoint proteins. They bind to proteins on the surface of other cells and can either stimulate or inhibit the activity of T-lymphocytes. Usually, the surface proteins of foreign cells lead to the activation of T cells against them, whereas the suppression of T cells is a built-in mechanism that prevents the immune system from attacking the body's own healthy cells.

However, tumor cells are able to outwit the immune system by synthesizing proteins that, when bound to the proteins of T-cell control points, cause their inhibition. In some cases, the interaction of tumor proteins with checkpoint proteins leads to the death of T cells. Different laboratories have tried to create checkpoint inhibitors that would counteract these suppressive interactions of proteins in order to reactivate the body's immune response against tumor cells. One of these drugs has already been approved by the US FDA for the treatment of metastatic melanoma, the rest are available or are being developed for the treatment of other malignancies.

But, despite significant achievements, it remains difficult to determine which cancer patients are shown this type of therapy and which drugs have the greatest potential. Solving these problems will contribute to determining the safest and most effective medicines for patients, as well as saving time and money. In order for it to be practical for clinical use, a method of rapid testing of a large number of immunotherapeutic drugs against living tumor cells is needed to obtain accurate and easily analyzed data.

A joint research team from the Terasaki Institute of Biomedical Innovation (TIBI) has successfully developed and tested such a system. First, they cultured spherical aggregates of breast cancer cells in a 3D-printed transparent chip with conical microlunks. These microlunks have been designed for optimal growth and stability of cellular spheres. Tests carried out on cellular spheres in microlunks confirmed the viability of cells and their production of surface proteins that deactivate T cells. The transparency of the chip allows for direct microscopic observations, and its design allows for a large number of tests, which is well suited for rapid screening of immunotherapeutic drugs.

To test the effectiveness of checkpoint protein-inhibiting drugs to activate the antitumor immune response, the team looked at how T-lymphocytes normally behave during activation: they produce cytokines that attract other immune cells to the danger detection site, stimulate their division and destruction of invaders. Thus, measuring the level of cytokines may indirectly indicate the degree of activation of T cells.

Researchers have created an effective automated system for measuring cytokine levels using microlunks loaded with cancer cells. Tests of this system were carried out using protein preparations-checkpoint inhibitors. The results showed that during incubation of breast cancer cells with T-lymphocytes, cytokine production increased after administration of drugs, demonstrating their effectiveness in activating antitumor immunity.

Another application of the chip was to evaluate the effect of cancer cells on activated T cells. The researchers labeled T cells with fluorescein and added them to breast cancer cells in microlunks; the transparency of the chip made it possible to directly observe their interaction using fluorescence microscopy. Breast cancer cells usually cause the rupture and death of T cells, but experiments conducted with checkpoint inhibitor drugs have shown that they increase the viability of T cells. The group clearly demonstrated how immune cells can resist attempts to destroy cancer cells.

Breast cancer on a chip was also used for direct observation of how T cells penetrate into the cellular spheres of cancer - the ability to infiltrate is a measure of antitumor activity and viability of T cells. After labeling each group of cells with separate dyes, the infiltration of T cells in the microlunks of the chip could be directly visualized using high-resolution fluorescence microscopy. Experiments conducted with checkpoint inhibitor drugs showed that in the presence of the drug, the number of T cells increased and they penetrated deeper into breast cancer cells.

Thus, the researchers have shown reliable and effective methods for assessing the interaction between tumor and immune cells, as well as fast, scalable and clinically significant screening methods for immunotherapeutic antitumor drugs. The microlunar chip and devices for working with it can also be used for other types of tumor cells and patient cells to predict the response to therapy, as well as for screening and development of new antitumor drugs.

Article by X.Jiang et al. Cancer on a Chip for Modeling Immune Checkpoint Inhibitor and Tumor Interactions is published in the journal Small.

Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of the Terasaki Institute: Breast Cancer-on-a-Chip For Testing Immunotherapy Drugs.