Paclitaxel Induces Immunogenic Cell Death in Ovarian Cancer via TLR4/IKK2/SNARE-Dependent Exocytosis

Abstract

Emerging evidence shows that the efficacy of chemotherapeutic drugs is reliant on their capability to induce immunogenic cell death (ICD), thus transforming dying tumor cells into antitumor vaccines. We wanted to uncover potential therapeutic strategies that target ovarian cancer by having a better understanding of the standard-ofcare chemotherapy treatment. Here, we showed in ovarian cancer that paclitaxel induced ICD-associated damage-associated molecular patterns (DAMP, such as CALR exposure, ATP secretion, and HMGB1 release) in vitro and elicited significant antitumor responses in tumor vaccination assays in vivo. Paclitaxel-induced TLR4 signaling was essential to the release of DAMPs, which led to the activation of NF-kB-mediated CCL2 transcription and IkappaB kinase 2-mediated SNARE-dependent vesicle exocytosis, thus exposing CALR on the cell surface. Paclitaxel induced endoplasmic reticulum stress, which triggered protein kinase R-like ER kinase activation and eukaryotic translation initiation factor 2a phosphorylation independent of TLR4. Paclitaxel chemotherapy induced T-cell infiltration in ovarian tumors of the responsive patients; CALR expression in primary ovarian tumors also correlated with patients' survival and patient response to chemotherapy. These findings suggest that the effectiveness of paclitaxel relied upon the activation of antitumor immunity through ICD via TLR4 and highlighted the importance of CALR expression in cancer cells as an indicator of response to paclitaxel chemotherapy in ovarian cancer.

Restoring the Immunity in the Tumor Microenvironment: Insights into Immunogenic Cell Death in Onco-Therapies

“…This report also shows a connection between a low dose of PTX and T cell recruitment and activation together with cytokine release in mice [ 87 ]. This study was corroborated by the report of Lau and collaborators that detailed the implication of TLR4 receptor in ICD induction by PTX with an entire description of the signaling pathways associated [ 88 ]. This work also showed DAMP release mediated by this antimitotic drug promoted ICD.…”

High Lymphocyte Population-related Predictive Factors for a Long-term Response in Non-small Cell Lung Cancer Patients Treated with Pemetrexed: A Retrospective Observational Study

“…These ndings support those of the present study and suggest that the high ALC population associated with long-term PEM-speci c responses are the result of T-cell-intrinsic mechanisms induced by PEM. PTX chemotherapy has also been reported to induce ICD-associated DAMPs and T-cell in ltration in ovarian tumors of responsive patients, suggesting that PTX also relies upon the activation of antitumor immunity [32]. However, PTX alone and in combination with carboplatin appears to reduce the immunomodulatory effects compared to PEM alone, suggesting the existence of PEM-speci c immune regulation [1].…”

Advances in Molecular Mechanisms for Traditional Chinese Medicine Actions in Regulating Tumor Immune Responses

“…Immune response of tumor cells is critical for tumor progression. Furthermore, cell death can trigger immune responses of nearby cells through releasing damage-associated molecular patterns (DAMPs), including cytokines or chemokines ( Lau et al., 2020 ). Accumulating evidence shows that TCM could enhance immune responses and protect from immune escape ( Table 4 ), and induce cell death of tumor cells ( Table 5 ).…”