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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
Screening of novel immunogenic cell death inducers within the NCI Mechanistic Diversity Set
Abdul Qader Sukkurwala1, Sandy Adjemian1, Laura Senovilla2
1Equipe 11 labellisée par la Ligue Nationale contre le cancer, Centre de Recherche des Cordeliers; Paris, France ; INSERM, U1138; Paris, France ; Gustave Roussy Comprehensive Cancer Center; Villejuif, France.
Abstract:
Immunogenic cell death (ICD) inducers can be defined as agents that exert cytotoxic effects while stimulating an immune response against dead cell-associated antigens. When initiated by anthracyclines, ICD is accompanied by stereotyped molecular changes, including the pre-apoptotic exposure of calreticulin (CRT) on the cell surface, the lysosomal secretion of ATP during the blebbing phase of apoptosis, and the release of high mobility group box 1 (HMGB1) from dead cells. By means of genetically engineered human osteosarcoma U2OS cells, we screened the 879 anticancer compounds of the National Cancer Institute (NCI) Mechanistic Diversity Set for their ability to promote all these hallmarks of ICD in vitro. In line with previous findings from our group, several cardiac glycosides exhibit a robust propensity to elicit the major manifestations of ICD in cultured neoplastic cells. This screen pointed to septacidin, an antibiotic produced by Streptomyces fibriatus, as a novel putative inducer of ICD. In low-throughput validation experiments, septacidin promoted CRT exposure, ATP secretion and HGMB1 release from both U2OS cells and murine fibrosarcoma MCA205 cells. Moreover, septacidin-killed MCA205 cells protected immunocompetent mice against a re-challenge with living cancer cells of the same type. Finally, the antineoplastic effects of septacidin on established murine tumors were entirely dependent on T lymphocytes. Altogether, these results underscore the suitability of the high-throughput screening system described here for the identification of novel ICD inducers.
Insights
Researchers identified septacidin, an antibiotic, as a novel inducer of immunogenic cell death (ICD). This discovery highlights a new strategy for cancer therapy by stimulating immune responses against tumors.
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- Immunogenic cell death (ICD) involves cytotoxic effects that stimulate immune responses against tumor antigens.
- Key hallmarks of ICD include calreticulin exposure, ATP secretion, and HMGB1 release.
- Anthracyclines are known inducers of ICD, providing a benchmark for identifying new agents.
Purpose of the Study:
- To screen a diverse set of anticancer compounds for their ability to induce ICD.
- To identify novel compounds that exhibit the hallmarks of immunogenic cell death.
- To validate the efficacy of a newly identified ICD inducer in preclinical cancer models.
Main Methods:
- Utilized genetically engineered human osteosarcoma U2OS cells for high-throughput screening.
- Screened 879 anticancer compounds from the NCI Mechanistic Diversity Set.
- Validated findings using in vitro assays for CRT exposure, ATP secretion, and HMGB1 release, followed by in vivo studies in mice.
Main Results:
- Cardiac glycosides showed a propensity to elicit ICD manifestations.
- Septacidin, an antibiotic from *Streptomyces fibriatus*, was identified as a novel putative ICD inducer.
- Septacidin promoted CRT exposure, ATP secretion, and HMGB1 release in cancer cells and demonstrated T-lymphocyte-dependent antineoplastic effects in mice.
Conclusions:
- The high-throughput screening system is effective for identifying novel ICD inducers.
- Septacidin represents a promising novel agent for cancer immunotherapy, inducing immunogenic cell death.
- The antineoplastic effects of septacidin are mediated by T lymphocytes, suggesting its potential in adoptive immunotherapy.
