Leveraging Immunogenic Cell Death to Enhance the Immune Response against Malignant Pleural Mesothelioma Tumors

Our plain-English summary of Leveraging Immunogenic Cell Death to Enhance the Immune Response against Malignant Pleural Mesothelioma Tumors, by M.R. Chang, E.M. Matnurov, C. Wu, et al (Journal of the American Chemical Society, 2025).

The study

• Authors: M.R. Chang, E.M. Matnurov, C. Wu, J. Arakelyan, H.J. Choe, V. Kushnarev, J.Y. Yap, X.X. Soo, M.J. Chow, W. Berger, W.H. Ang, M.V. Babak
• Journal: Journal of the American Chemical Society
• Published: 2025;147(9):7908-7920
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Although various metal-based compounds have exhibited excellent immunogenic cell death (ICD)-inducing properties both in vitro and in vivo, the majority of these compounds have been discovered serendipitously. In this work, we have successfully synthesized and characterized 35 cyclometalated Au(III) complexes containing dithiocarbamate ligands, with 25 of these complexes being previously unreported. Their ability to induce phagocytosis in vitro against immunologically "cold" malignant pleural mesothelioma (MPM) cells was strongly dependent on the cyclometalated scaffold and the overall lipophilicity of the complexes. We elucidated the role of cell death mechanisms in the observed ICD effects and identified correlations between the ability of the complexes to induce necrotic cell death and ICD, both in vitro and in vivo. Complex 2G, with its high phagocytosis rates and low necrosis rates, was recognized as a bona fide ICD inducer, demonstrating a remarkably long-lasting immune response in vaccinated mice. In contrast, complex 1C, characterized by high phagocytosis rates and high necrosis rates, failed to elicit a sustained immune response upon following vaccination; however, it triggered selective activation of calreticulin in tumors upon direct in vivo administration. Overall, this study offers a framework for predicting ICD effects in vivo for structurally similar Au(III) complexes, with the potential for extension to other series of metal complexes.

In plain English

This laboratory and animal study did not examine asbestos exposure or people. The authors made 35 gold(III) compounds, 25 of them new, and tested whether they kill malignant pleural mesothelioma cells in a way that prompts an immune response (immunogenic cell death). In a 72-hour viability test on mesothelioma cell lines, all compounds showed cytotoxicity at 0.053 to 8.4 micromolar. In mice with AB12 mesothelioma tumors, six compounds given every second day, and cisplatin-pemetrexed, reduced tumor burden versus carrier-treated mice. In an earlier daily-dosing toxicity test, two mice died in the 5H group and one in the 5F group. In cell experiments, more fat-soluble compounds were associated with more uptake of treated cancer cells by macrophages (immune cells). Of eight mice vaccinated with 2G-treated cancer cells and then injected with live cancer cells, seven stayed tumor-free for 164 days and four for 210 days. Within 30 days, about half the mice given only PBS (a salt solution) or cells treated with 1C, 2C, 4C or 5C developed tumors. The authors concluded that 2G induced a robust, long-lasting immune response in mice.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory chemistry and cell-culture study with mouse experiments (tumor treatment and vaccination experiments)
• Who was studied: Seven mesothelioma-related cell lines: one murine malignant mesothelioma line (AB12), five human malignant mesothelioma lines (JU77, LO68, VMC23, Meso84, Meso92) and one human nonmalignant line (Met5A). Three of these lines (VMC23, Meso84, Meso92) came from surgical specimens of patients with MPM. Also BALB/c mice, n = 8 per group in the vaccination experiment.
• Exposure: No asbestos exposure was studied. The cells and mice were exposed to 35 cyclometalated gold(III) dithiocarbamate complexes, compared with cisplatin and pemetrexed. In mouse tumor studies, the doses were 5G at 8 mg/kg; 5A, 5B, 5C and 5H at 4 mg/kg; and 5F at 2.5 mg/kg, given every second day.
• Main results:
  • In a 72-hour MTT cell-viability assay on seven cell lines, all gold complexes showed cytotoxicity in the range of 0.053 to 8.4 micromolar. Cisplatin was cytotoxic at 2 to 20 micromolar and pemetrexed at 0.023 to 0.3 micromolar.
  • In AB12 tumor-bearing mice treated every second day, all tested complexes and the cisplatin-pemetrexed combination reduced tumor burden compared with vehicle-treated mice. One 5A-treated mouse showed complete remission.
  • In the preliminary toxicity study, daily injections (given for 5A, 5H and 5F) caused toxicity. Two mice died in group 5H and one in group 5F. Mice injected every second day showed no signs of toxicity, and the tumor study then used every-second-day dosing.
  • Phagocytosis of treated AB12 cells by macrophages was highest for 1C (41% plus or minus 5%). Cisplatin and pemetrexed did not initiate an immunogenic cell death response. The order of lipophilicity (fat-solubility) of the complexes matched their phagocytosis levels.
  • In the vaccination experiment, 7 of 8 mice vaccinated with 2G-treated cells remained tumor-free for 164 days, and 4 of 8 for 210 days.
  • Within the first 30 days after vaccination, about 50% of mice given PBS or vaccinated with complexes 1C, 2C, 4C and 5C developed tumors. Four of eight mice vaccinated with pemetrexed developed tumors by Day 51.
  • When given directly to tumor-bearing mice, 2G caused no tumor necrosis, while 1C caused significant necrosis. 1C raised calreticulin in non-necrotic tumor tissue but not in liver or kidney.
• The authors' conclusion: The authors concluded that they identified a gold(III) complex (2G) that induced a robust immune response in mice for more than half a year. They also concluded that their findings show how in vitro screening may predict which compounds induce immunogenic cell death in vivo.
• Limitations the authors state:
  • Cultured macrophages were highly sensitive to the gold complexes, suggesting possible toxicity to immune cells. The authors note, however, that macrophage numbers in treated tumors did not differ.
  • The biomolecular targets of the compounds remain to be identified.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Phagocytosis, Necrosis.

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