Tumor-associated macrophage-derived inflammatory cytokine enhances malignant potential of malignant pleural mesothelioma

Our plain-English summary of Tumor-associated macrophage-derived inflammatory cytokine enhances malignant potential of malignant pleural mesothelioma, by D. Horio, T. Minami, H. Kitai, et al (Cancer Science, 2020).

The study

• Authors: D. Horio, T. Minami, H. Kitai, H. Ishigaki, Y. Higashiguchi, N. Kondo, S. Hirota, K. Kitajima, Y. Nakajima, Y. Koda, E. Fujimoto, Y. Negi, M. Niki, S. Kanemura, E. Shibata, K. Mikami, R. Takahashi, T. Yokoi, K. Kuribayashi, T. Kijima
• Journal: Cancer Science
• Published: 2020;111(8):2895-2906
• Cited by: 23 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an asbestos-related aggressive malignant neoplasm. Due to the difficulty of achieving curative surgical resection in most patients with MPM, a combination chemotherapy of cisplatin and pemetrexed has been the only approved regimen proven to improve the prognosis of MPM. However, the median overall survival time is at most 12 mo even with this regimen. There has been therefore a pressing need to develop a novel chemotherapeutic strategy to bring about a better outcome for MPM. We found that expression of interleukin-1 receptor (IL-1R) was upregulated in MPM cells compared with normal mesothelial cells. We also investigated the biological significance of the interaction between pro-inflammatory cytokine IL-1β and the IL-1R in MPM cells. Stimulation by IL-1β promoted MPM cells to form spheroids along with upregulating a cancer stem cell marker CD26. We also identified tumor-associated macrophages (TAMs) as the major source of IL-1β in the MPM microenvironment. Both high mobility group box 1 derived from MPM cells and the asbestos-activated inflammasome in TAMs induced the production of IL-1β, which resulted in enhancement of the malignant potential of MPM. We further performed immunohistochemical analysis using clinical MPM samples obtained from patients who were treated with the combination of platinum plus pemetrexed, and found that the overexpression of IL-1R tended to correlate with poor overall survival. In conclusion, the interaction between MPM cells and TAMs through a IL-1β/IL-1R signal could be a promising candidate as the target for novel treatment of MPM (Hyogo College of Medicine clinical trial registration number: 2973).

© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

In plain English

This laboratory study examined how immune cells called tumor-associated macrophages might make malignant pleural mesothelioma cells more aggressive. It used human mesothelioma cell lines, a normal mesothelial cell line and macrophages grown from THP-1 cells. In one mesothelioma cell line, H2452, a signaling protein called IL-1β did not change how fast the cells multiplied in flat (two-dimensional) culture. In a separate three-dimensional test, it did increase the formation of cell clusters (spheroids). It also raised CD26, a marker of cancer stem cells, in these cells. When CD26 levels were reduced (knocked down), the cells formed fewer spheroids. Macrophages grown alongside H2452 cells made more IL-1β and raised CD26 in the cancer cells. An antibody against IL-1β blocked this rise. The experiments themselves did not use asbestos. The authors also stained tumor samples from 21 patients treated with platinum plus pemetrexed. Median overall survival was 407 days in the group with low IL-1 receptor and 237 days in the group with high IL-1 receptor, but the difference was not statistically significant. The authors concluded that targeting this macrophage–tumor signal is a promising treatment strategy.

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 (cell-culture) experiment, combined with a small tissue-staining and survival analysis of patient samples
• Who was studied: Four human malignant pleural mesothelioma cell lines, one human mesothelial cell line (Met-5A) and THP-1-derived macrophages. Also tumor samples from 21 patients with malignant pleural mesothelioma treated with platinum plus pemetrexed, collected by surgical biopsy at Hyogo College of Medicine Hospital, Japan, from August 2017 to September 2018. The patients were 20 men and 1 woman; 16 tumors were epithelioid, 2 biphasic and 3 sarcomatoid.
• Exposure: In the laboratory, mesothelioma cells were exposed to recombinant IL-1β (10 ng/mL) or grown alongside macrophages. No asbestos was used in the experiments, and no fiber types are named. Asbestos's role in the authors' proposed model comes from earlier studies. Table 1 lists the patients' asbestos exposure as occupational in 14, environmental in 3 and unknown in 4.
• Main results:
  • IL-1 receptor (IL-1R) expression was higher in the mesothelioma cell lines than in the normal mesothelial cell line Met-5A. IL-1β expression in the mesothelioma cells was very low.
  • In H2452 mesothelioma cells, IL-1β did not affect cell proliferation in two-dimensional culture.
  • In a separate sphere-formation assay, the number of secondary spheroids formed by H2452 cells increased significantly with IL-1β.
  • IL-1β raised the cancer stem cell marker CD26 on H2452 cells over time.
  • The IL-1β-induced rise in CD26 was blocked by an AP-1 inhibitor but not by an NF-κB inhibitor.
  • Knocking down (reducing) CD26 in H2452 cells with either of two siRNAs significantly reduced the number of spheroids compared with control.
  • When THP-1-derived macrophages were grown together with H2452 mesothelioma cells, the macrophages' IL-1β expression rose significantly.
  • CD26 expression in H2452 cells rose when they were grown with the macrophages.
  • The co-culture rise in CD26 was significantly blocked by an antibody that neutralizes IL-1β.
  • Knocking down caspase-1 (part of the inflammasome) in the macrophages significantly reduced the co-culture rise in CD26 in H2452 cells.
  • Among the 21 patients, median progression-free survival was 161 days in the low-IL-1R group (n = 11) and 110 days in the high-IL-1R group (n = 10).
  • Median overall survival was 407 days in the low-IL-1R group and 237 days in the high-IL-1R group.
  • The differences in progression-free and overall survival between the low- and high-IL-1R groups were not statistically significant.
  • Disease control rate was 72.7% in the low-IL-1R group and 60.0% in the high-IL-1R group (Table 2), with no significant difference.
  • No statistically significant correlation was found between IL-1R score and the proportion of activated macrophages (AIF-1-positive cells) in the patient samples.
• The authors' conclusion: The authors concluded that tumor-associated macrophages play a critical role in the progression of malignant pleural mesothelioma. They considered targeting the IL-1β/IL-1R interaction between these macrophages and mesothelioma cells a promising new treatment strategy.

Topics

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

Medical terms in this study, explained in our Lexicon: Macrophage, Cytokine, Pleural Mesothelioma, Neoplasm, Surgical Resection, Chemotherapy, Cisplatin, Pemetrexed (Alimta).

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