Immunogenic Cell Death for Tumors

Pre-screening compounds in vitro can accelerate the discovery and development of therapeutic regimens that kill malignant cells in an immunogenic fashion

Normal apoptosis is a process that goes largely unnoticed by the immune system. However, certain chemotherapeutic agents are able to trigger a type of apoptotic cell death that also induces an effective anti-tumor response by the adaptive immune system, called “immunogenic cell death” (ICD).

ICD relies on the establishment of stress responses that promote the spatiotemporally coordinated emission of endogenous danger signals from dying cells. These signals are known as damage-associated molecular patterns (DAMPs). Three DAMPs are recognized as vital for the ICD of cancer cells: calreticulin (CRT), which is exposed on the cell surface, the secretion of ATP and passively-released high mobility group protein B1 (HMGB1).

Several anti-cancer agents that have been successfully employed in the clinic for decades, such as oxaliplatin, cyclophosphamide and paclitaxel, have since been found to elicit active immunological anti-tumour responses via ICD. However, if the chemotherapeutic agent fails to induce one (or more) of these DAMPs, then the ICD response is completely compromised.

The gold-standard approach to evaluate the ability of a specific agent to ICD relies on vaccination assays involving immunocompetent murine tumor models and cancer cells pre-treated in vitro. Malignant cells are exposed to the test compound in vitro and then inoculated subcutaneously into mice. One week later, untreated, live cancer cells of the same type are injected. If the compound successfully induces ICD, then the vaccinated mice will have developed immunity against the cancer cells and will not develop tumors. The proportion of mice that do not develop tumors reflects the degree of ICD induced.

Clearly, in vivo testing is incompatible with the high-throughput screening of new compounds. Since the molecular characteristics of ICD are well established, it is possible to screen large numbers of compounds in vitro with cultured cancer cells using calreticulin, ATP and HMGB1 as surrogate markers of ICD. Compounds that successfully induce all three of these markers in vitro could then be progressed to confirmatory testing, namely the in vivo vaccination assay described above. Thus, pre-screening compounds in vitro can accelerate the discovery and development of therapeutic regimens that kill malignant cells in an immunogenic fashion, and reduce the unnecessary use of mice.

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Aug 21, 2018 |
Elisa Masat

Immunogenic Cell Death for Tumors

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