Damage-Associated Molecular Patterns (DAMPs) related to Immunogenic Cell Death are differentially triggered by clinically relevant chemotherapeutics in lung adenocarcinoma cells

Abstract

Background Chemotherapeutics can stimulate immune antitumor response by inducing immunogenic cell death (ICD), which is characterized by the appearance of Damage-Associated Molecular Patterns (DAMPs) like the exposure of calreticulin (CRT) in cell surface, the release of ATP and the secretion of High Mobility Group Box 1 (HMGB1). Methods Here, our objective was to investigate levels of ICD-associated DAMPs induced by chemotherapeutics commonly used in the clinical practice of non-small cell lung cancer (NSCLC) and the prognosis values of these DAMPs.A549 human lung adenocarcinoma cells were treated with cisplatin, carboplatin, etoposide, paclitaxel and gemcitabine using clinically relevant conditions (doses, times and co-treatments). We assessed ICD-associated DAMPs, cell viability, apoptosis and autophagy in an integrated way. Results We found that cisplatin induced the highest levels of apoptosis, while carboplatin and etoposide were the less cytotoxic. Cisplatin also induced the highest levels of ICD-associated DAMPs, which was not incremented by co-treatments. Etoposide induced the lower levels of ICD and the highest levels of autophagy, suggesting that the cytoprotective role of autophagy is dominant in relation to its pro-ICD role. High levels of CRT were associated with better prognosis in TCGA databank. In an integrative analysis we found a strong negative correlation between cell number and ICD-associated DAMPs as well as between autophagy and ICD-associated DAMPs. We also purpose a mathematical integration of ICD-associated DAMPs in an index (InDAMPs) that may represent with greater biological relevance this process. Conclusions Cisplatin alone induced the highest levels of ICD-associated DAMPs, so that its combination with immunotherapies can be a promising therapeutic strategy in NSCLC.

CXCR4-Targeted Macrophage-Derived Biomimetic Hybrid Vesicle Nanoplatform for Enhanced Cancer Therapy through Codelivery of Manganese and Doxorubicin

“…In the context of cancer immunotherapy, immunogenic cell death (ICD) is a key regulatory pathway in which damage-associated molecular patterns (DAMPs) released from dying cells function as danger signals to stimulate immune responses for antitumor activities. Some chemotherapeutic drugs, such as doxorubicin (Dox) and oxaliplatin (OXA), have been widely used in cancer immunotherapy for their ability to induce ICD-related immunogenicity, which makes these drugs attractive components in combination therapies. − Recently, as an alternative to conventional therapeutic modalities, metalloimmunotherapy has been explored extensively as a potential strategy to activate host immunity by supplementing the TME with nutritional metal ions. − As an important intracellular ion, manganese (Mn 2+ ) has been reported to activate cGAS-STING signaling, promote immune cell activation, and serve as an adjuvant to improve the antitumor efficacy of immunotherapy. , Nonetheless, despite the expanded understanding of metalloimmunotherapy, the development of an innovative biomimetic delivery platform that can mediate combinational therapy between ICD and metal ions is needed urgently.…”