Detection of Circulating Biomarkers of Immunogenic Cell Death After Radiotherapy and Chemotherapy: An Exploratory Study

The main aim of anticancer therapies is to exert cytotoxic effects on cancer cells. It recently emerged that some anticancer therapeutic modalities are capable of inducing a cell death subroutine called immunogenic cell death (ICD) that can mediate specific, sustained anticancer immunity. These observations have marked the beginning of intense research into immunoadjuvant or anticancer immunity inducing "side-effects" associated with anticancer therapies.

At present, in humans, no ICD-associated predictive biomarkers have been identified, which hampers the development of immunological strategies. No published data about human biomarkers for ICD is available.

In vitro, ICD has been found to be associated with the spatiotemporally defined emission of danger signals such as surface exposed calreticulin (CRT) or heat shock protein 90 (HSP90), secreted ATP and released TLR4 agonists like HMGB1 or HSP70. Moreover, recently it has emerged that ICD may also be associated with a "viral response-like chemokine signature (VCS)" capable of acting as both 'find me' signal (for granulocytic myeloid cells) and 'keep away' signal (for immature monocytic myeloid cells) - further details of this paradigm are under investigation.

Thus, the presence of these molecular determinants of ICD can be used to monitor the host immune status and as a predictive biomarker. Examples include: danger signals as surrogate positive biomarkers (HMGB1, HSP70 and autoantibodies against CRT/HSP90); viral-response like chemokine signature as direct positive biomarkers (IFN1A, IFN1B and CXCL10>CCL2>CXCL1).

The presence of determinants of ICD can be confirmed through the strategy of following biomarkers (in non-hematological cancers):