Building a Bridge between Chemotherapy and Immunotherapy in Malignant Pleural Mesothelioma: Investigating the Effect of Chemotherapy on Immune Checkpoint Expression

Our plain-English summary of Building a Bridge between Chemotherapy and Immunotherapy in Malignant Pleural Mesothelioma: Investigating the Effect of Chemotherapy on Immune Checkpoint Expression, by E. Marcq, J.R.V. Audenaerde, J. Waele, et al (International Journal of Molecular Sciences, 2019).

The study

• Authors: E. Marcq, J.R.V. Audenaerde, J. Waele, J. Jacobs, J.V. Loenhout, G. Cavents, P. Pauwels, J.P.V. Meerbeeck, E.L. Smits
• Journal: International Journal of Molecular Sciences
• Published: 2019;20(17)
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

In light of the promising results of immune checkpoint blockade (ICPB) in malignant pleural mesothelioma (MPM), we investigated the effect of different chemotherapeutic agents on the expression of immune checkpoints (ICPs) in order to rationally design a good treatment schedule for their combination with ICP blocking antibodies. Cisplatin, oxaliplatin and pemetrexed are interesting chemotherapeutic agents to combine with immunotherapy given their immunomodulatory capacities. We looked into cisplatin and pemetrexed because their combination is used as first-line treatment of MPM. Additionally, the effect of the immunogenic chemotherapeutic agent, oxaliplatin, was also studied. Three different MPM cell lines were used for representation of both epithelioid and sarcomatoid subtypes. The desired inhibitory concentrations of the chemotherapeutic agents were determined with the SRB-assay. Allogeneic co-cultures of MPM cells with healthy donor peripheral blood mononuclear cells (PBMC) were set up to assess the effect of these chemotherapeutic agents on the expression of ICPs (PD-1, LAG-3, TIM-3) and their ligands (PD-L1, PD-L2, galectin-9). Cisplatin might be a promising treatment to combine with ICP blocking antibodies since our MPM cell lines were most susceptible to this stand-alone treatment. We found that the expression of ICPs and their ligands on both MPM cells and PBMC was mostly downregulated or unaltered when treated with chemotherapeutic agents, though no clear trend could be determined.

In plain English

This was a laboratory study on cancer cells grown in dishes, not on patients, and it did not study asbestos exposure. The authors tested three chemotherapy drugs (cisplatin, oxaliplatin and pemetrexed) and the cisplatin plus pemetrexed combination on three malignant pleural mesothelioma cell lines. Two lines were epithelioid (NCI-H2818, NCI-H2795) and one was sarcomatoid (NCI-H2731). NCI-H2818 cells were significantly more sensitive to cisplatin and oxaliplatin than the other two lines. None of the three lines responded to pemetrexed. Cisplatin plus pemetrexed did not significantly change cell survival compared with untreated cells or with the other treatments. The authors then grew the cancer cells together with blood immune cells from healthy donors. They measured immune checkpoint molecules (PD-1, LAG-3, TIM-3) and their partner molecules (PD-L1, PD-L2, galectin-9). The only statistically significant change was in TIM-3 on immune cells grown with NCI-H2731 after cisplatin (p = 0.037). The authors concluded that expression was mostly lowered or unchanged but showed no clear trend. They said no solid conclusion could be drawn about the best timing for combining chemotherapy and immunotherapy.

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: In vitro laboratory experiment: drug sensitivity testing of mesothelioma cell lines, then co-cultures of these cells with healthy donor blood immune cells analysed by flow cytometry
• Who was studied: Three immortalised human malignant pleural mesothelioma cell lines provided by the Netherlands Cancer Institute: two epithelioid (NCI-H2818, NCI-H2795) and one sarcomatoid (NCI-H2731). Blood immune cells (PBMC) came from healthy donors, with a different donor for each experiment. Experiments were done in Antwerp, Belgium. No human patients were studied.
• Exposure: No asbestos exposure was studied. The cells were treated with chemotherapy drugs: cisplatin and oxaliplatin (each tested at 0 to 50 micromolar), pemetrexed (0 to 10 micromolar) and cisplatin plus pemetrexed, for 72 hours. Co-culture experiments used low (IC20) concentrations. The pemetrexed concentration (0.05 micromolar) was taken from earlier work in the authors' lab on other, pemetrexed-sensitive cancer cell lines.
• Main results:
  • NCI-H2818 was significantly more sensitive to cisplatin and oxaliplatin than NCI-H2731 (p = 0.007 and p = 0.030) and NCI-H2795 (p = 0.008 and p = 0.001). The concentrations giving 50% survival were: cisplatin 2.31 (NCI-H2818), 7.78 (NCI-H2795) and 7.89 (NCI-H2731); oxaliplatin 3.47, 18.23 and 9.77, respectively.
  • None of the three cell lines responded to pemetrexed.
  • At IC20 concentrations, all lines showed about 20% lower cell survival after cisplatin. However, there were no significant differences in survival after any treatment, including cisplatin plus pemetrexed, compared with untreated cells or between treatments.
  • In the co-cultures, the only significant change in immune checkpoint expression was in the percentage of TIM-3-positive immune cells (PBMC) grown with NCI-H2731 after cisplatin (p = 0.037). The text does not state the direction of this change.
  • There was a trend, not statistically significant, toward lower immune checkpoint expression in two of the three cell lines after cisplatin, oxaliplatin or pemetrexed. This was not seen in the third cell line.
• The authors' conclusion: The authors concluded that immune checkpoint and ligand expression on mesothelioma cells and immune cells was mostly lowered or unchanged by chemotherapy, with no clear trend. They suggested that giving checkpoint-blocking antibodies before chemotherapy might be preferable. They stated that expression seems very dynamic and likely patient-dependent, and that more research is needed to define a treatment schedule.
• Limitations the authors state:
  • A different healthy blood donor was used for each experiment, which may explain the variation in immune checkpoint expression on immune cells.
  • The lack of a combined effect of cisplatin and pemetrexed may reflect limitations of the laboratory model.
  • The authors could not rule out that chemotherapy changed how the measured molecules respond to trypsin, the enzyme used to detach the cells. They said results should ideally be compared with another detection method.
  • Immune checkpoint expression appeared very dynamic and is likely patient-dependent.

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: Chemotherapy, Immunotherapy, Pleural Mesothelioma, Cisplatin, Pemetrexed (Alimta), Epithelioid, Sarcomatoid, PD-L1.

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