Researchers Use Tumor Slices to Understand Microenvironment, Test Therapeutics

Tumor slices provide a useful platform for studying the tumor microenvironment and evaluating the preclinical efficacy of cancer therapeutics, according to a recent study.

The researchers described using organotypic tumor slice cultures for the study of the tumor immune microenvironment and the response to immune-modulatory drugs. These tumor slice cultures provide an opportunity to study tumor cell behavior in the context of an intact microenvironment and native extracellular matrix.

This gives them an advantage over cultured cell-based approaches. Although cultured cell systems provide high-throughput capability within a simplified cellular context, the lack of the native tumor microenvironment makes them more limited.

Another alternative, synthetic tissue systems called organoids, incorporate basic features of tissue architecture; they have the advantage of including cells within a more physiological and morphologically complex context. However, they have a lower throughput capability than that of cell culture systems and take a long time to generate.

Many cell types—immune cells, endothelial cells, cancer cells—as well as morphological structures, such as blood and lymph vessels, in the native tumor slice can be visualized using fluorescently conjugated antibodies and live-tissue imaging. Until now, tumor slices mostly have been used to test the effect of cytotoxic drugs primarily on the cancer cells in the slice.

Using flow cytometry-based immunophenotyping, researchers characterized the immune cell composition in organotypic tumor slices prepared from 4 mouse tumor models and a human liver tumor. They phenotyped tumor-infiltrating CD45+ leukocytes of both the tumor cores and the tumor slices by multiplex flow cytometry to understand the immune composition of these slices and how similar they are to that of the original tumors. They then monitored the immune cells in slices from subcutaneous mouse pancreatic or breast tumors over 7 days to understand how these populations change over time.

After the overall cell viability initially declined, the percentage of CD45+ cells in the total viable cells was stable from days 3 to 7 after harvest. Among the CD45+ cells, macrophages were the predominant type of immune cell in the slices, similar to the immune cells detected in many human solid tumors.

Using the mouse pancreatic and colon cancer cell models and a clinically resected liver tumor sample, the researchers found that the immune cells in the slices responded predictably to an immunomodulator, interferon γ and the anti—programmed death-ligand 1 checkpoint inhibitor blockade

Using samples from patient-derived xenograft tumors, they compared organotypic tumor slices with organoid cultures from the same xenograft, and they found that many responses to cytotoxic drugs and targeted therapies in organotypic tumor slices are similar to the responses of the matched organoids. Some differences were observed, primarily in the lymphocyte population of a clinical hepatocellular carcinoma case.

Researchers said mouse tumor slices for assessing responses to immune-modulatory agents are possible, as well using patient-derived xenograft tumor slices for assessing responses to targeted and cytotoxic drugs.

“Systematic characterization of the tumor slice culture system will enable its effective application for translational research,” the authors wrote.

Reference

Sivakumar R, Chan M, Shin JS. Organotypic tumor slice cultures provide a versatile platform for immuno-oncology and drug discovery [published online October 10]. Oncoimmunology. doi:10.1080/2162402X.2019.1670019.